JP5937201B2 - 2-Amino-3- (imidazol-2-yl) pyridin-4-one derivatives and their use as VEGF receptor kinase inhibitors - Google Patents
2-Amino-3- (imidazol-2-yl) pyridin-4-one derivatives and their use as VEGF receptor kinase inhibitors Download PDFInfo
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- JP5937201B2 JP5937201B2 JP2014510800A JP2014510800A JP5937201B2 JP 5937201 B2 JP5937201 B2 JP 5937201B2 JP 2014510800 A JP2014510800 A JP 2014510800A JP 2014510800 A JP2014510800 A JP 2014510800A JP 5937201 B2 JP5937201 B2 JP 5937201B2
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- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 title description 4
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Description
本発明はVEGF受容体のキナーゼ活性の阻害剤である7−フェノール又は7−アルキニル−3−(イミダゾール−2−イル)−1,8−ナフチリジン−4−オン誘導体とその可能なキノリノンアナログ、その製造及び治療薬としてのその使用に関する。 The present invention relates to 7-phenol or 7-alkynyl-3- (imidazol-2-yl) -1,8-naphthyridin-4-one derivatives and their possible quinolinone analogs, which are inhibitors of the kinase activity of the VEGF receptor, It relates to its manufacture and its use as a therapeutic.
VEGF(血管内皮細胞増殖因子)ファミリーの蛋白質はVEGF−R1(Flt−1)、VEGF−R2(KDR)及びVEGF−R3(Flt−4)と呼ばれる3種の構造的に同類の受容体チロシンキナーゼと結合する。3種の受容体はいずれも胚形成中及び腫瘍誘導性血管新生中の脈管構造の発生に不可欠である。更に、VEGFR−3はリンパ系の発生と腫瘍誘導性リンパ管新生にも重要な役割を果たす。 The VEGF (vascular endothelial growth factor) family of proteins consists of three structurally related receptor tyrosine kinases called VEGF-R1 (Flt-1), VEGF-R2 (KDR) and VEGF-R3 (Flt-4) Combine with. All three receptors are essential for the development of vasculature during embryogenesis and tumor-induced angiogenesis. In addition, VEGFR-3 plays an important role in the development of the lymphatic system and tumor-induced lymphangiogenesis.
特に、WO2009/007535はVEGF受容体のキナーゼ活性の阻害剤である置換7−アルキニル−4−オキソ−1,8−ナフチリジン−3−カルボキサミド誘導体について記載している。本発明の化合物は少なくとも二環系の3位にイミダゾール環を有する点において従来技術のこれらの化合物と相違する。 In particular, WO 2009/007535 describes substituted 7-alkynyl-4-oxo-1,8-naphthyridine-3-carboxamide derivatives that are inhibitors of the kinase activity of the VEGF receptor. The compounds of the present invention differ from these prior art compounds in that they have an imidazole ring at least at the 3-position of the bicyclic system.
薬物化合物の開発において考慮すべき条件は化合物の組織暴露とその効力である。これらの条件は効力、吸収、分布、代謝、排泄及び毒性のうちの少なくとも1項目を改善することにより向上させることができる。 Conditions to consider in the development of a drug compound are the tissue exposure of the compound and its efficacy. These conditions can be improved by improving at least one of efficacy, absorption, distribution, metabolism, excretion and toxicity.
VEGF受容体のキナーゼ活性の高活性阻害剤を入手することが依然として必要であり、これは本発明の新規化合物により有利に達成される。 There remains a need to obtain highly active inhibitors of VEGF receptor kinase activity, which is advantageously achieved by the novel compounds of the present invention.
本発明の第1の対象は下記一般式(I)に対応する化合物に関する。 The first object of the present invention relates to a compound corresponding to the following general formula (I).
本発明の別の対象は一般式(I)の化合物の製造方法に関する。 Another subject of the present invention relates to a process for the preparation of compounds of general formula (I).
本発明の別の対象は特に医薬又は医薬組成物における一般式(I)の化合物の使用に関する。 Another subject of the present invention relates in particular to the use of a compound of general formula (I) in a medicament or pharmaceutical composition.
本発明の化合物は一般式(I): The compounds of the present invention have the general formula (I):
−Wは窒素原子又はCH基を表し;
−Yは1個以上のハロゲン原子を表すR7で場合により置換された、C2−C3アルキニレン基、1,4−フェニレン基を表し;
−Zは結合又はCR1R2基を表し;
−R1及びR2は相互に独立して場合により1個以上のハロゲン原子で置換された、水素原子、C1−C6アルキル基、トリフルオロメチル基、(CH2)nOR6基、C3−C7シクロアルキル基、ヘテロアリール基もしくはアリール基から選択される基を表し;
−R1及びR2はそれらを担持している炭素原子と一緒になってC3−C7シクロアルキル基を形成してもよく;
−R3は水素原子を表し;
−R4は場合によりC3−C7シクロアルキル基で置換された、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基又はC1−C6アルキル基から選択される基を表し;
−R5は水素原子又はC1−C6アルキル基から選択される基を表し;
−R6は水素原子又はC1−C6アルキル基から選択される基を表し;
−nは1、2又は3である。
-W represents a nitrogen atom or a CH group;
-Y is optionally substituted with R 7 representing a 1 or more halogen atom, C 2 -C 3 alkynylene group, a 1,4-phenylene group;
-Z represents a bond or a CR 1 R 2 group;
-R 1 and R 2 are each independently a hydrogen atom, a C 1 -C 6 alkyl group, a trifluoromethyl group, a (CH 2 ) n OR 6 group, optionally substituted with one or more halogen atoms, C 3 -C 7 cycloalkyl group, represents a group selected from heteroaryl or aryl group;
-R 1 and R 2 together with the carbon atom carrying them may form a C 3 -C 7 cycloalkyl group;
-R 3 represents a hydrogen atom;
-R 4 are substituted by C 3 -C 7 cycloalkyl group optionally, C 1 -C 6 alkyl, (CH 2) n OR 6 group, C 3 -C 7 cycloalkyl group or a C 1 -C 6 Represents a group selected from alkyl groups;
-R 5 represents a group selected from hydrogen atom or a C 1 -C 6 alkyl group;
-R 6 represents a group selected from hydrogen atom or a C 1 -C 6 alkyl group;
-N is 1, 2 or 3.
式(I)の化合物は1個以上の不斉炭素原子を含んでいてもよい。従って、前記化合物はエナンチオマー又はジアステレオマーとして存在していてもよい。これらのエナンチオマー及びジアステレオマーと、ラセミ混合物を含めたその混合物も本発明に含まれる。 The compound of formula (I) may contain one or more asymmetric carbon atoms. Thus, the compounds may exist as enantiomers or diastereomers. These enantiomers and diastereomers and mixtures thereof including racemic mixtures are also included in the present invention.
式(I)の化合物は塩基として存在していてもよいし、酸付加塩として存在していてもよい。このような付加塩も本発明に含まれる。 The compound of formula (I) may exist as a base or may exist as an acid addition salt. Such addition salts are also included in the present invention.
これらの塩は医薬的に許容可能な酸を用いて製造することができるが、例えば式(I)の化合物を精製又は単離するために有用な他の酸の塩も本発明に含まれる。 These salts can be prepared using pharmaceutically acceptable acids, but other acid salts useful, for example, for purifying or isolating compounds of formula (I) are also included in the invention.
本発明に関しては、以下の定義を適用する。
−ハロゲン原子:フッ素、塩素、臭素又はヨウ素原子。
−Ct−Cz:可能な炭素原子数tからzの炭素鎖であり、t及びzは1から7の値をとることができ、例えば、C1−C3は可能な炭素原子数1から3の炭素鎖である。
−アルキル:直鎖又は分岐鎖飽和脂肪族基。例としては、メチル基、エチル基、n−プロピル基、イソプロピル基、ブチル基、イソブチル基、tert−ブチル基、ペンチル基等が挙げられる。
−アルキレン:アルカン鎖の2個の末端炭素原子から各々水素原子を1個ずつ除去することにより誘導され、場合によりアルキル基で置換された2価基であり、例えばC1−C3アルキレン基は炭素原子数1から3の直鎖又は分岐鎖2価炭素鎖を表し、より特定的にはメチレン基、エチレン基、メチルエチレン基又はプロピレン基が挙げられる。
−アルケニレン:アルケン鎖の2個の末端炭素原子から各々水素原子を1個ずつ除去することにより誘導され、場合によりアルキル基又はアルケニル基で置換された2価基であり、例えばC2−C3アルケニレン基は炭素原子数2から3の直鎖又は分岐鎖2価炭素鎖を表し、より特定的にはエテニレン基又はプロペニレン基が挙げられる。
−アルキニレン:アルキン鎖の2個の末端炭素原子から各々水素原子を1個ずつ除去することにより誘導され、場合によりアルキル基、アルケニル基又はアルキニル基で置換された2価基であり、例えばC2−C3アルキニレン基は炭素原子数2から3の直鎖又は分岐鎖2価炭素鎖を表し、より特定的にはエチニレン基又はプロピニレン基が挙げられる。
−シクロアルキル:飽和又は部分不飽和環状アルキル基。例としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロプロペニル基、シクロブテニル基、シクロペンテニル基、シクロヘキセニル基等が挙げられる。
−シクロアルコキシ:−O−シクロアルキル基であり、ここでシクロアルキル基は上記に定義した通りである。
−フルオロアルキル:1個以上の水素原子をフッ素原子に置き換えたアルキル基。
−アルコキシ:−O−アルキル基であり、ここでアルキル基は上記に定義した通りである。
−フルオロアルコキシ:1個以上の水素原子をフッ素原子に置き換えたアルコキシ基。
−チオアルキルないしアルキルチオ:−S−アルキル基であり、ここでアルキル基は上記に定義した通りである。
−アリール:炭素原子数6から10の単環式又は二環式芳香族基。アリール基の例としてはフェニル基とナフチル基が挙げられる。
−アリーレン:アリールから2個の環炭素原子の水素原子を1個ずつ除去することにより誘導される2価基。アリーレン基の例としてはフェニレン基が挙げられる。
−複素環:O、S及びNから選択される1から3個のヘテロ原子を含む飽和又は部分不飽和5から7員単環式基。複素環の例としてはアゼチジニル、ピペリジル、アゼピニル、モルホリニル、チオモルホリニル、ピペラジニル、ホモピペラジニル、ジヒドロオキサゾリル、ジヒドロチアゾリル、ジヒドロイミダゾリル、ジヒドロピロリル又はテトラヒドロピリジル、[1,3]ジオキソリル、[1,3]ジオキシニル、ジヒドロ[1,4]ジオキシニル、ジヒドロ[1,2]オキサジニル、ジヒドロ[1,3]オキサジニル、ジヒドロオキサゾリル、ジヒドロイソオキサゾリル、ジヒドロ[1,4]オキサジニル、テトラヒドロ[1,3]オキサゼピニル、テトラヒドロ[1,4]オキサゼピニル、テトラヒドロ[1,3]ジアゼピニル及びテトラヒドロ[1,4]ジアゼピニルが挙げられる。
−ヘテロアリール:O、S及びNから選択される1から5個のヘテロ原子を含む5から12員単環式又は二環式芳香族基。単環式ヘテロアリールの例としては、イミダゾリル、ピラゾリル、チアゾリル、オキサゾリル、イソチアゾリル、イソオキサゾリル、フリル、チエニル、オキサジアゾリル、チアジアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル及びトリアジニルが挙げられる。二環式ヘテロアリールの例としては、インドリル、イソインドリル、ベンゾフリル、ベンゾチオフェニル、ベンゾオキサゾリル、ベンゾイミダゾリル、インダゾリル、ベンゾチエニル、イソベンゾフリル、イソベンゾチアゾリル、ピロロ[2,3−c]ピリジル、ピロロ[2,3−b]ピリジル、ピロロ[3,2−b]ピリジル、ピロロ[3,2−c]ピリジル、ピロロ[1,2−a]ピリジル、キノリル、イソキノリル、シンノリニル、キナゾリニル、キノキサリニル、ピロロ[1,2−a]イミダゾリル、イミダゾ[1,2−a]ピリジル、イミダゾ[1,2−a]ピリダジニル、イミダゾ[1,2−c]ピリミジニル、イミダゾ[1,2−a]ピリミジニル、イミダゾ[1,2−a]ピラジニル、イミダゾ[4,5−b]ピラジニル、イミダゾ[4,5−b]ピリジル、イミダゾ[4,5−c]ピリジル、ピラゾロ[2,3−a]ピリジル、ピラゾロ[2,3−a]ピリミジニル、ピラゾロ[2,3−a]ピラジニル、チアゾロ[5,4−b]ピリジル、チアゾロ[5,4−c]ピリジル、チアゾロ[4,5−c]ピリジル、チアゾロ[4,5−b]ピリジル、オキサゾロ[5,4−b]ピリジル、オキサゾロ[5,4−c]ピリジル、オキサゾロ[4,5−c]ピリジル、オキサゾロ[4,5−b]ピリジル、イソチアゾロ[5,4−b]ピリジル、イソチアゾロ[5,4−c]ピリジル、イソチアゾロ[4,5−c]ピリジル、イソチアゾロ[4,5−b]ピリジル、イソオキサゾロ[5,4−b]ピリジル、イソオキサゾロ[5,4−c]ピリジル、イソオキサゾロ[4,5−c]ピリジル及びイソオキサゾロ[4,5−b]ピリジルが挙げられる。
−「オキソ」は「=O」を意味する。
−「チオ」は「−S−」を意味する。
For the present invention, the following definitions apply:
-Halogen atom: A fluorine, chlorine, bromine or iodine atom.
-C t -C z: a possible carbon chain number t of z carbon atoms, t and z can take values from 1 to 7, for example, C 1 -C 3 Possible 1 -C To 3 carbon chains.
-Alkyl: linear or branched saturated aliphatic group. Examples include methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group and the like.
- alkylene: derived by each removal of a hydrogen atom by one to two terminal carbon atoms of the alkane chain, optionally a divalent group substituted by an alkyl group, for example C 1 -C 3 alkylene group A linear or branched divalent carbon chain having 1 to 3 carbon atoms is represented, and more specifically, a methylene group, an ethylene group, a methylethylene group, or a propylene group can be mentioned.
Alkenylene: a divalent group derived by removing one hydrogen atom from each of the two terminal carbon atoms of the alkene chain and optionally substituted with an alkyl or alkenyl group, for example C 2 -C 3 The alkenylene group represents a straight or branched divalent carbon chain having 2 to 3 carbon atoms, and more specifically includes an ethenylene group or a propenylene group.
-Alkynylene: a divalent group derived by removing one hydrogen atom from each of the two terminal carbon atoms of the alkyne chain and optionally substituted with an alkyl, alkenyl or alkynyl group, for example C 2 The —C 3 alkynylene group represents a straight or branched divalent carbon chain having 2 to 3 carbon atoms, and more specifically includes an ethynylene group or a propynylene group.
-Cycloalkyl: a saturated or partially unsaturated cyclic alkyl group. Examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group and the like.
-Cycloalkoxy: -O-cycloalkyl group, wherein the cycloalkyl group is as defined above.
-Fluoroalkyl: an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms.
-Alkoxy: an -O-alkyl group, wherein the alkyl group is as defined above.
-Fluoroalkoxy: an alkoxy group in which one or more hydrogen atoms are replaced by fluorine atoms.
-Thioalkyl or alkylthio: -S-alkyl group, wherein the alkyl group is as defined above.
-Aryl: monocyclic or bicyclic aromatic group having 6 to 10 carbon atoms. Examples of the aryl group include a phenyl group and a naphthyl group.
-Arylene: A divalent group derived by removing one hydrogen atom of two ring carbon atoms from aryl. An example of an arylene group is a phenylene group.
-Heterocycle: a saturated or partially unsaturated 5- to 7-membered monocyclic group containing 1 to 3 heteroatoms selected from O, S and N. Examples of heterocycles include azetidinyl, piperidyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, dihydropyrrolyl or tetrahydropyridyl, [1,3] dioxolyl, [1, 3] Dioxinyl, dihydro [1,4] dioxinyl, dihydro [1,2] oxazinyl, dihydro [1,3] oxazinyl, dihydrooxazolyl, dihydroisoxazolyl, dihydro [1,4] oxazinyl, tetrahydro [1 , 3] oxazepinyl, tetrahydro [1,4] oxazepinyl, tetrahydro [1,3] diazepinyl and tetrahydro [1,4] diazepinyl.
-Heteroaryl: a 5- to 12-membered monocyclic or bicyclic aromatic group containing 1 to 5 heteroatoms selected from O, S and N. Examples of monocyclic heteroaryl include imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, furyl, thienyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl. Examples of bicyclic heteroaryl include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothienyl, isobenzofuryl, isobenzothiazolyl, pyrrolo [2,3-c] Pyridyl, pyrrolo [2,3-b] pyridyl, pyrrolo [3,2-b] pyridyl, pyrrolo [3,2-c] pyridyl, pyrrolo [1,2-a] pyridyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, Quinoxalinyl, pyrrolo [1,2-a] imidazolyl, imidazo [1,2-a] pyridyl, imidazo [1,2-a] pyridazinyl, imidazo [1,2-c] pyrimidinyl, imidazo [1,2-a] Pyrimidinyl, imidazo [1,2-a] pyrazinyl, imidazo [4,5-b] pyrazinyl, Midazo [4,5-b] pyridyl, imidazo [4,5-c] pyridyl, pyrazolo [2,3-a] pyridyl, pyrazolo [2,3-a] pyrimidinyl, pyrazolo [2,3-a] pyrazinyl, Thiazolo [5,4-b] pyridyl, thiazolo [5,4-c] pyridyl, thiazolo [4,5-c] pyridyl, thiazolo [4,5-b] pyridyl, oxazolo [5,4-b] pyridyl, Oxazolo [5,4-c] pyridyl, oxazolo [4,5-c] pyridyl, oxazolo [4,5-b] pyridyl, isothiazolo [5,4-b] pyridyl, isothiazolo [5,4-c] pyridyl, Isothiazolo [4,5-c] pyridyl, isothiazolo [4,5-b] pyridyl, isoxazolo [5,4-b] pyridyl, isoxazolo [5,4-c] pyridyl, isoxazolo [ , 5-c] pyridyl, and isoxazolo [4,5-b] include pyridyl.
“Oxo” means “═O”.
-"Thio" means "-S-".
本発明に関しては、以下の略語及び式を使用する。
Boc tert−ブチルオキシカルボニル
CuI ヨウ化銅(I)
CH2Cl2 ジクロロメタン
HPLC 高性能液体クロマトグラフィー
LC/MS 液体クロマトグラフィー質量分析法
dba ジベンジリデンアセトン
DCM ジクロロメタン
DME ジメトキシエタン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
dppf 1,1’−ビス(ジフェニルホスフィノ)フェロセン
℃ 摂氏
Et3N トリエチルアミン
h 時間
HCl 塩酸
IR 赤外線
MeOH メタノール
min. 分
ml ミリリットル
MgSO4 硫酸マグネシウム
NaCl 塩化ナトリウム
NH4Cl 塩化アンモニウム
NH4OH 水酸化アンモニウム
NaHCO3 炭酸水素ナトリウム
Na2SO4 硫酸ナトリウム
NMR 核磁気共鳴
Rt 保持時間
SEM [2−(トリメチルシリル)エトキシ]メチル
THF テトラヒドロフラン
TOSMIC トシルメチルイソシアニド
トリチル トリフェニルメチル
Xphos 2−ジシクロヘキシルホスフィノ−2’,4’,6’−トリイソプロピルビフェニル。
For the present invention, the following abbreviations and formulas are used.
Boc tert-Butyloxycarbonyl CuI Copper iodide (I)
CH 2 Cl 2 dichloromethane HPLC high performance liquid chromatography LC / MS liquid chromatography mass spectrometry dba dibenzylideneacetone DCM dichloromethane DME dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide dppf 1,1′-bis (diphenylphosphino) ferrocene ° C. Et 3 N triethylamine h time HCl hydrochloric acid IR infrared MeOH methanol min. Minute ml Milliliter MgSO 4 Magnesium sulfate NaCl Sodium chloride NH 4 Cl Ammonium chloride NH 4 OH Ammonium hydroxide NaHCO 3 Sodium bicarbonate Na 2 SO 4 Sodium sulfate NMR Nuclear magnetic resonance Rt Retention time SEM [2- (Trimethylsilyl) ethoxy] methyl THF Tetrahydrofuran TOSMIC Tosylmethyl isocyanide trityl triphenylmethyl Xphos 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl.
本発明の対象である一般式(I)の化合物のうち、第1のサブグループの化合物はWが窒素原子又はCH基を表す化合物により構成される。 Among the compounds of general formula (I) that are the subject of the present invention, the compounds of the first subgroup are constituted by compounds in which W represents a nitrogen atom or a CH group.
本発明の対象である一般式(I)の化合物のうち、第2のサブグループの化合物はWが窒素原子を表す化合物により構成される。 Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the second subgroup are composed of compounds in which W represents a nitrogen atom.
本発明の対象である一般式(I)の化合物のうち、第3のサブグループの化合物はYがC2−C3アルキニレン基、より特定的にはエチニレン基を表す化合物により構成される。 Among the compounds of general formula (I) that are the subject of the present invention, the compounds of the third subgroup are constituted by compounds in which Y represents a C 2 -C 3 alkynylene group, more specifically an ethynylene group.
本発明の対象である一般式(I)の化合物のうち、第4のサブグループの化合物は、
−Zが結合、CR1R2基を表し;
−R1が場合により1個以上のハロゲン原子で置換された、水素原子、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基、アリール基又は5員もしくは6員ヘテロアリール基から選択される基を表し;
−R2が水素原子、C1−C6アルキル基又はトリフルオロメチル基から選択される基を表し;
−R6が水素原子又はC1−C6アルキル基から選択される基を表し;
−nが1、2又は3である
化合物により構成される。
Of the compounds of general formula (I) that are the subject of the present invention, compounds of the fourth subgroup are:
-Z represents a bond, a CR 1 R 2 group;
—R 1 optionally substituted with one or more halogen atoms, a hydrogen atom, a C 1 -C 6 alkyl group, a (CH 2 ) n OR 6 group, a C 3 -C 7 cycloalkyl group, an aryl group or 5 Represents a group selected from a membered or 6-membered heteroaryl group;
-R 2 represents a group selected from hydrogen atom, C 1 -C 6 alkyl or trifluoromethyl groups;
Represents a group -R 6 are selected from hydrogen atom or a C 1 -C 6 alkyl group;
It is constituted by a compound in which n is 1, 2 or 3.
本発明の対象である一般式(I)の化合物のうち、第5のサブグループの化合物は、
−ZがCR1R2基を表し;
−R1が水素原子、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基、アリール基又は5員もしくは6員ヘテロアリール基から選択される基を表し;
−R2が水素原子、C1−C6アルキル基又はトリフルオロメチル基から選択される基を表し;
−R6が水素原子又はC1−C6アルキル基から選択される基を表し;
−nが1、2又は3である
化合物により構成される。
Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the fifth subgroup are:
-Z represents a CR 1 R 2 group;
-R 1 is hydrogen atom, C 1 -C 6 alkyl, a (CH 2) n OR 6 group, C 3 -C 7 cycloalkyl group, an aryl group or a 5-membered or 6-membered group selected from a heteroaryl group Representation;
-R 2 represents a group selected from hydrogen atom, C 1 -C 6 alkyl or trifluoromethyl groups;
Represents a group -R 6 are selected from hydrogen atom or a C 1 -C 6 alkyl group;
It is constituted by a compound in which n is 1, 2 or 3.
YがC2−C3アルキニレン基、より特定的にはエチニレン基を表すとき、ZはCR1R2基を表し、R1及びR2は上記に定義した通りである。 Y is C 2 -C 3 alkynylene group, when more specifically representing the ethynylene group, Z is represents CR 1 R 2 group, R 1 and R 2 are as defined above.
本発明の対象である一般式(I)の化合物のうち、第6のサブグループの化合物は、R4が場合によりC3−C7シクロアルキル基で置換された、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基又はC1−C6アルキル基から選択される基を表す化合物により構成される。 Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the sixth subgroup are C 1 -C 6 alkyl groups, wherein R 4 is optionally substituted by a C 3 -C 7 cycloalkyl group , (CH 2 ) n OR 6 group, C 3 -C 7 cycloalkyl group or C 1 -C 6 alkyl group.
本発明の対象である一般式(I)の化合物のうち、第7のサブグループの化合物は、R4がC1−C6アルキル基、より特定的にはエチル基を表す化合物により構成される。 Among the compounds of the general formula (I) that are the subject of the present invention, the compounds of the seventh subgroup are composed of compounds in which R 4 represents a C 1 -C 6 alkyl group, more specifically an ethyl group. .
本発明の対象である一般式(I)の化合物のうち、第8のサブグループの化合物は、R5が水素原子又は1−C6アルキル基から選択される基を表す化合物により構成される。 Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the eighth subgroup are constituted by compounds in which R 5 represents a group selected from a hydrogen atom or a 1- C 6 alkyl group.
本発明の対象である一般式(I)の化合物のうち、第9のサブグループの化合物はR5が水素原子を表す化合物により構成される。 Among the compounds of general formula (I) that are the subject of the present invention, the compounds of the ninth subgroup are composed of compounds in which R 5 represents a hydrogen atom.
本発明の対象である一般式(I)の化合物のうち、第10のサブグループの化合物はW、Y、Z、R3、R4及びR5の上記定義を組合せた化合物により構成される。 Among the compounds of general formula (I) that are the subject of the present invention, the compounds of the tenth subgroup are composed of compounds that combine the above definitions of W, Y, Z, R 3 , R 4 and R 5 .
本発明の対象である一般式(I)の化合物のうち、第11のサブグループの化合物は、
−Wが窒素原子又はCH基を表し;
−Yが場合によりハロゲン原子で置換された、C2−C3アルキニレン基又は1,4−フェニレン基を表し;
−Zが結合、CR1R2基を表し;
−R1が場合によりハロゲン原子で置換された、水素原子、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基、アリール基又は5員もしくは6員ヘテロアリール基から選択される基を表し;
−R2が水素原子、C1−C6アルキル基又はトリフルオロメチル基から選択される基を表し;
−R3が水素原子を表し;
−R4が場合によりC3−C7シクロアルキル基で置換された、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基又はC1−C6アルキル基から選択される基を表し;
−R5が水素原子又はC1−C6アルキル基から選択される基を表し;
−R6が水素原子又はC1−C6アルキル基から選択される基を表し;
−nが1、2又は3である
化合物により構成される。
Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the eleventh subgroup
-W represents a nitrogen atom or a CH group;
-Y is substituted with a halogen atom optionally represents a C 2 -C 3 alkynylene group or a 1,4-phenylene group;
-Z represents a bond, a CR 1 R 2 group;
—R 1 optionally substituted with a halogen atom, a hydrogen atom, a C 1 -C 6 alkyl group, a (CH 2 ) n OR 6 group, a C 3 -C 7 cycloalkyl group, an aryl group, or a 5 or 6 member Represents a group selected from heteroaryl groups;
-R 2 represents a group selected from hydrogen atom, C 1 -C 6 alkyl or trifluoromethyl groups;
-R 3 is hydrogen;
-R 4 is substituted with a C 3 -C 7 cycloalkyl group optionally, C 1 -C 6 alkyl, (CH 2) n OR 6 group, C 3 -C 7 cycloalkyl group or a C 1 -C 6 Represents a group selected from alkyl groups;
-R 5 are radicals represents a group selected from hydrogen atom or a C 1 -C 6 alkyl group;
Represents a group -R 6 are selected from hydrogen atom or a C 1 -C 6 alkyl group;
It is constituted by a compound in which n is 1, 2 or 3.
本発明の対象である一般式(I)の化合物のうち、第12のサブグループの化合物は、
−Wが窒素原子又はCH基を表し;
−YがC2−C3アルキニレン基を表し;
−ZがCR1R2基を表し;
−R1が場合によりハロゲン原子で置換された、水素原子、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基、アリール基又は5員もしくは6員ヘテロアリール基から選択される基を表し;
−R2が水素原子、C1−C6アルキル基又はトリフルオロメチル基から選択される基を表し;
−R3が水素原子を表し;
−R4が場合によりC3−C7シクロアルキル基で置換された、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基又はC1−C6アルキル基から選択される基を表し;
−R5が水素原子又はC1−C6アルキル基から選択される基を表し;
−R6が水素原子又はC1−C6アルキル基から選択される基を表し;
−nが1、2又は3である
化合物により構成される。
Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the twelfth subgroup are:
-W represents a nitrogen atom or a CH group;
-Y represents a C 2 -C 3 alkynylene group;
-Z represents a CR 1 R 2 group;
—R 1 optionally substituted with a halogen atom, a hydrogen atom, a C 1 -C 6 alkyl group, a (CH 2 ) n OR 6 group, a C 3 -C 7 cycloalkyl group, an aryl group, or a 5 or 6 member Represents a group selected from heteroaryl groups;
-R 2 represents a group selected from hydrogen atom, C 1 -C 6 alkyl or trifluoromethyl groups;
-R 3 is hydrogen;
-R 4 is substituted with a C 3 -C 7 cycloalkyl group optionally, C 1 -C 6 alkyl, (CH 2) n OR 6 group, C 3 -C 7 cycloalkyl group or a C 1 -C 6 Represents a group selected from alkyl groups;
-R 5 are radicals represents a group selected from hydrogen atom or a C 1 -C 6 alkyl group;
Represents a group -R 6 are selected from hydrogen atom or a C 1 -C 6 alkyl group;
It is constituted by a compound in which n is 1, 2 or 3.
本発明の対象である一般式(I)の化合物のうち、第13のサブグループの化合物は、R1及びR2がそれらを担持している炭素原子と一緒になってC3−C7シクロアルキル基を形成する化合物により構成される。 Of the compounds of general formula (I) that are the subject of the present invention, compounds of the thirteenth subgroup are those in which R 1 and R 2 together with the carbon atom carrying them are C 3 -C 7 cyclo It is comprised by the compound which forms an alkyl group.
当然のことながら、上記サブグループを各々他のサブグループの1以上と組合せてもよく、対応する化合物も本発明の対象とする。 Of course, each of the above subgroups may be combined with one or more of the other subgroups, and the corresponding compounds are also the subject of the present invention.
本発明の対象である一般式(I)の化合物のうち、特に以下の化合物を挙げることができる。
1:2−アミノ−1−エチル−7−((3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
2:2−アミノ−1−プロピル−7−((3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
3:2−アミノ−7−(3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
4:2−アミノ−1−エチル−7−(3−ヒドロキシ−3−ピリジン−2−イルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
5:2−アミノ−1−エチル−7−[(3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イン−1−イル]−3−(4−メチル−1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
6:2−アミノ−1−(シクロプロピルメチル)−7−(3−ヒドロキシペンタ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
7:2−アミノ−1−エチル−7−[(3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イン−1−イル]−3−(1H−イミダゾール−2−イル)キノリン−4(1H)−オン
8:2−アミノ−7−(3−クロロ−4−ヒドロキシフェニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
9:2−アミノ−1−エチル−7−[3−(2−フルオロフェニル)−3−ヒドロキシブタ−1−イン−1−イル]−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
10:2−アミノ−1−シクロペンチル−7−(3−ヒドロキシペンタ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
11:2−アミノ−7−(3−ヒドロキシペンタ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1−(3−メトキシプロピル)−1,8−ナフチリジン−4(1H)−オン
12:2−アミノ−7−(3−ヒドロキシペンタ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1−(2−メトキシエチル)−1,8−ナフチリジン−4(1H)−オン
13:2−アミノ−1−エチル−7−[(1−ヒドロキシシクロブチル)エチニル]−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
14:2−アミノ−1−エチル−7−[(1−ヒドロキシシクロペンチル)エチニル]−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
15:2−アミノ−1−エチル−7−(3−ヒドロキシ−3−メチルブタ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
16:2−アミノ−1−エチル−7−(3−ヒドロキシ−3−メチルペンタ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
17:2−アミノ−1−エチル−7−(3−ヒドロキシ−3−フェニルブタ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
18:2−アミノ−1−エチル−7−[3−(3−フルオロフェニル)−3−ヒドロキシブタ−1−イン−1−イル]−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
19:2−アミノ−1−エチル−3−(1H−イミダゾール−2−イル)−7−(4,4,4−トリフルオロ−3−ヒドロキシ−3−フェニルブタ−1−イン−1−イル)−1,8−ナフチリジン−4(1H)−オン
20:2−アミノ−7−(3−シクロプロピル−3−ヒドロキシブタ−1−イン−1−イル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
21:2−アミノ−1−エチル−7−[3−ヒドロキシ−3−(チオフェン−2−イル)ブタ−1−イン−1−イル]−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
22:2−アミノ−1−エチル−7−(3−ヒドロキシブタ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
23:2−アミノ−1−エチル−7−(3−ヒドロキシペンタ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
24:2−アミノ−1−エチル−7−(3−ヒドロキシヘキサ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
25:2−アミノ−1−エチル−7−(3−ヒドロキシ−4−メチルペンタ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
26:2−アミノ−1−エチル−7−(3−ヒドロキシ−3−フェニルプロパ−1−イン−1−イル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
27:2−アミノ−7−((3R)−3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
28:2−アミノ−7−((3S)−3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
29:2−アミノ−1−エチル−7−((3S)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン。
Among the compounds of the general formula (I) that are the subject of the present invention, the following compounds can be mentioned in particular.
1: 2-amino-1-ethyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1 , 8] naphthyridin-4-one 2: 2-amino-1-propyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazole-2 -Yl) -1H- [1,8] naphthyridin-4-one 3: 2-amino-7- (3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazole) -2-yl) -1H- [1,8] naphthyridin-4-one 4: 2-amino-1-ethyl-7- (3-hydroxy-3-pyridin-2-ylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1, ] Naphthyridin-4-one 5: 2-amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-in-1-yl] -3- (4-methyl) -1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 6: 2-amino-1- (cyclopropylmethyl) -7- (3-hydroxypent-1-yne-1- Yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 7: 2-amino-1-ethyl-7-[(3R) -3-hydroxy-4- Methoxy-3-methylbut-1-in-1-yl] -3- (1H-imidazol-2-yl) quinolin-4 (1H) -one 8: 2-amino-7- (3-chloro-4-hydroxy Phenyl) -1-ethyl-3- (1H-imidazo -2-yl) -1,8-naphthyridin-4 (1H) -one 9: 2-amino-1-ethyl-7- [3- (2-fluorophenyl) -3-hydroxybut-1-yne-1 -Yl] -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 10: 2-amino-1-cyclopentyl-7- (3-hydroxypent-1-yne- 1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 11: 2-amino-7- (3-hydroxypent-1-yn-1-yl ) -3- (1H-imidazol-2-yl) -1- (3-methoxypropyl) -1,8-naphthyridin-4 (1H) -one 12: 2-amino-7- (3-hydroxypenta-1 -In-1-yl) -3- (1H-imidazole- 2-yl) -1- (2-methoxyethyl) -1,8-naphthyridin-4 (1H) -one 13: 2-amino-1-ethyl-7-[(1-hydroxycyclobutyl) ethynyl] -3 -(1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 14: 2-amino-1-ethyl-7-[(1-hydroxycyclopentyl) ethynyl] -3- (1H- Imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 15: 2-amino-1-ethyl-7- (3-hydroxy-3-methylbut-1-in-1-yl) -3 -(1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 16: 2-amino-1-ethyl-7- (3-hydroxy-3-methylpent-1-yne-1- Il) -3- (1H-imidazo Ru-2-yl) -1,8-naphthyridin-4 (1H) -one 17: 2-amino-1-ethyl-7- (3-hydroxy-3-phenylbut-1-in-1-yl)- 3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 18: 2-amino-1-ethyl-7- [3- (3-fluorophenyl) -3-hydroxybuta -1-In-1-yl] -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 19: 2-amino-1-ethyl-3- (1H-imidazole) -2-yl) -7- (4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-in-1-yl) -1,8-naphthyridin-4 (1H) -one 20: 2-Amino-7- (3-cyclopropyl-3-hydroxybuta- -In-1-yl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 21: 2-amino-1-ethyl-7- [3 -Hydroxy-3- (thiophen-2-yl) but-1-in-1-yl] -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 22: 2 -Amino-1-ethyl-7- (3-hydroxybut-1-yn-1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 23: 2-Amino-1-ethyl-7- (3-hydroxypent-1-yn-1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 24 : 2-amino-1-ethyl-7- (3-hydroxyhex-1-y N-1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 25: 2-amino-1-ethyl-7- (3-hydroxy-4- Methylpent-1-in-1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 26: 2-amino-1-ethyl-7- (3- Hydroxy-3-phenylprop-1-in-1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 27: 2-amino-7-(( 3R) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 28: 2- Amino-7-((3S) -3,4-dihydroxy-3-methyl Rubut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 29: 2-amino-1-ethyl-7-((3S ) -3-Hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one.
以下の文中において、「脱離基」なる用語は不均一結合が切断されて電子対を失うことにより分子から容易に開裂することができる基を意味する。従って、この基は例えば置換反応中に別の基で容易に置き換えることができる。このような脱離基は例えばハロゲンや、メタンスルホネート、ベンゼンスルホネート、p−トルエンスルホネート、トリフレート、アセテート等の活性化ヒドロキシル基である。脱離基の例とその製造に関する記載については“Advances in Organic Chemistry”,J.March,5th Edition,Wiley Interscience,2001を参照されたい。 In the text below, the term “leaving group” means a group that can be easily cleaved from a molecule by breaking a heterogeneous bond and losing an electron pair. Thus, this group can be easily replaced with another group, for example during a substitution reaction. Such leaving groups are, for example, activated hydroxyl groups such as halogen, methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate and the like. For examples of leaving groups and a description of their preparation, see “Advanceds in Organic Chemistry”, J. Am. See March, 5th Edition, Wiley Interscience, 2001.
以下の文中において、「保護基」(PG)なる用語は反応中に分子の一部を一時的に不活性化させる目的で化学構造に一時的に導入することができ、その後の合成工程で容易に除去できる基を意味する。保護基の例とその性質に関する記載については“Protective Groups in Organic Synthesis”,T.W.Greene,P.G.M.Wutz,3rd Edition,Wiley Interscience 1999を参照されたい。 In the text below, the term “protecting group” (PG) can be temporarily introduced into a chemical structure for the purpose of temporarily deactivating a portion of the molecule during the reaction, and can be easily used in subsequent synthetic steps. Means a group which can be removed. For examples of protecting groups and a description of their properties, see “Protective Groups in Organic Synthesis”, T.W. W. Greene, P.M. G. M.M. See Wutz, 3rd Edition, Wiley Interscience 1999.
本発明によると、一般式(I)の化合物は下記一般スキーム1、2及び3に示す方法に従って製造することができる。 According to the present invention, compounds of general formula (I) can be prepared according to the methods shown in the following general schemes 1, 2 and 3.
スキーム1によると、工程(i)では、室温又は通常の加熱もしくはマイクロ波加熱により50℃から100℃の温度にてアルコール(例えばエタノール、n−ブタノール、tert−ブタノール)や水等のプロトン性溶媒中で式(II)の2,6−ジハロゲノニコチン酸の2位を式R4−NH2(式中、R4は式(I)の化合物について上記に定義した通りである)のアミンでモノ置換する。工程(i)から得られた酸(III)を次に工程(ii)に従い、G.OlahらによりSynthesis(1973),487に記載されているように、トリエチルアミンやピリジン等の塩基の存在下、室温にてジクロロメタンやTHF等の非プロトン性溶媒中でフッ化シアヌルの作用により酸フッ化物として、又はDMFやTHF等の極性非プロトン性溶媒中でカルボニルジイミダゾールの作用によりイミダゾリドとして、あるいはMukaiyama and TanakaによりChem.Lett.(1976),303又はIshikawa and SasakiによりChem.Lett.(1976),1407に記載されている方法等の当業者に公知の他の方法により活性化させ、式(IV)の誘導体とする。 According to Scheme 1, in step (i), a protic solvent such as alcohol (eg, ethanol, n-butanol, tert-butanol) or water at room temperature or at a temperature of 50 ° C. to 100 ° C. by normal heating or microwave heating. In which the 2-position of 2,6-dihalogenonicotinic acid of formula (II) is an amine of formula R 4 —NH 2 , wherein R 4 is as defined above for the compound of formula (I) Mono-substitution. The acid (III) obtained from step (i) is then prepared according to step (ii) according to G. As described by Olah et al. In Synthesis (1973), 487, acid fluorides by the action of cyanuric fluoride in an aprotic solvent such as dichloromethane or THF at room temperature in the presence of a base such as triethylamine or pyridine. Or as an imidazolide by the action of carbonyldiimidazole in a polar aprotic solvent such as DMF or THF, or by Mukaiyama and Tanaka, Chem. Lett. (1976), 303 or Ishikawa and Sasaki, Chem. Lett. (1976), 1407, and other methods known to those skilled in the art to obtain the derivative of formula (IV).
式(V)のシアノメチルイミダゾールは無置換又はイミダゾールの(4,5)位を置換したイミダゾール−2−カルボキシアルデヒドから2段階で製造される。工程(iii)では、例えば“Protective Groups in Organic Synthesis”,Greene et al.,3rd Edition(John Wiley & Sons,Inc.,New York)に記載されているような当業者に公知の通常の操作条件下でイミダゾール−2−カルボキシアルデヒドの遊離窒素をスキーム1にPGで示す保護基(例えばSEM基、Boc基又はトリチル基)により保護する。妥当な場合には、保護イミダゾールのτ及びπの2種類の異性体が得られ、その後の反応では無差別に使用する。次に、工程(iv)では、低温(−50℃)のTOSMICの無水DME溶液にカリウムtert−ブチレートを加えることにより形成されたTOSMICのアニオンとアルデヒド官能基を反応させた後、形成されたアニオン性中間体である4−トシル−2−オキサゾリンを開環し、次にVan Leusen A.ら(Synthetic Comm,10(5)1980,399−403)により記載されている方法に従い、反応混合物をメタノールの存在下で加熱還流してアセチルニトリル官能基を形成することにより、保護イミダゾール−2−カルボキシアルデヒドを式(V)のシアノメチルイミダゾールに変換する。 The cyanomethylimidazole of formula (V) is prepared in two steps from imidazole-2-carboxaldehyde which is unsubstituted or substituted at the (4,5) position of imidazole. In step (iii), for example, “Protective Groups in Organic Synthesis”, Greene et al. Protecting the free nitrogen of imidazole-2-carboxaldehyde with PG in Scheme 1 under normal operating conditions known to those skilled in the art, as described in, 3rd Edition (John Wiley & Sons, Inc., New York) Protected by a group (eg SEM group, Boc group or trityl group). When appropriate, two isomers of protected imidazole, τ and π, are obtained and used indiscriminately in subsequent reactions. Next, in step (iv), the anion of TOSMIC formed by adding potassium tert-butyrate to an anhydrous DSM solution of TOSMIC at a low temperature (−50 ° C.) is reacted with the aldehyde functional group, and then the formed anion. Ring opening of 4-tosyl-2-oxazoline, which is a functional intermediate, followed by Van Leusen A. et al. (Synthetic Comm, 10 (5) 1980, 399-403), the reaction mixture is heated to reflux in the presence of methanol to form the acetyl nitrile functional group, thereby protecting the protected imidazole-2- Carboxaldehyde is converted to cyanomethylimidazole of formula (V).
工程(ii)後に得られる式(IV)の酸フッ化物又はイミダゾリドは非常に反応性であるが、安定しており、これを次に工程(v)で水素化ナトリウムやカリウムtert−ブトキシド等の塩基1当量の存在下、−5℃から室温までの温度にてTHFやDMF等の極性非プロトン性溶媒中で式(V)の無置換又は(4,5)位置換シアノメチルイミダゾールと反応させた後、先に使用した塩基を更に1当量加え、形成された式(VI)の化合物を工程(vi)に従い、室温にてin situ環化し、式(VII)のピリジノ−ピリジノン化合物を得る。 The oxyfluoride or imidazolide of formula (IV) obtained after step (ii) is very reactive but stable, which is then converted in step (v) such as sodium hydride or potassium tert-butoxide. Reaction with an unsubstituted or (4,5) -substituted cyanomethylimidazole of the formula (V) in a polar aprotic solvent such as THF or DMF at a temperature from −5 ° C. to room temperature in the presence of 1 equivalent of a base. Then, another equivalent of the base used previously is added, and the formed compound of formula (VI) is cyclized in situ at room temperature according to step (vi) to obtain the pyridino-pyridinone compound of formula (VII).
スキーム2によると、工程(vii)では、ピリジン等の塩基の存在下、室温又は通常の加熱もしくはマイクロ波加熱により50℃から100℃の温度にて水等のプロトン性溶媒中で過マンガン酸カリウム等の強酸化剤を使用することにより、あるいは米国特許第6,187,950号に記載の方法等の当業者に公知の他の方法により、式(VIII)の2,4−ジハロゲノトルエンを酸化させ、対応する酸誘導体(IX)とする。工程(vii)から得られた酸(IX)の2位を室温又は通常の加熱もしくはマイクロ波加熱により50℃から100℃の温度にてアルコール(例えばエタノール、n−ブタノール、tert−ブタノール)や水等のプロトン性溶媒中で式R4−NH2(式中、R4は式(I)の化合物について上記に定義した通りである)のアミンでモノ置換する。工程(viii)から得られた酸(X)を次に室温又は通常の加熱もしくはマイクロ波加熱により50℃から120℃の温度にてDMF、トルエン、THF、ジオキサン等の非プロトン性溶媒中でカルボニルジイミダゾール又はトリホスゲンの作用により環化し、ベンゾ−1,3−オキサジン−2,4−ジオン(XI)とする。次にベンゾ−1,3−オキサジン−2,4−ジオン(XI)をトリエチルアミンやピリジン等の塩基の存在下、室温又は通常の加熱もしくはマイクロ波加熱により50℃から120℃の温度にてDMF、トルエン、ジオキサン等の非プロトン性溶媒中で、あるいはIminovらによりSynthesis(2008)1535に記載されている方法等の当業者に公知の他の方法によりマロノニトリルで処理し、ニトリル(XII)を得る。工程(x)から得られたこのニトリル(XII)をCuCl等の銅触媒の存在下、室温又は通常の加熱もしくはマイクロ波加熱により50℃から120℃の温度にてDME、DMF、トルエン、ジオキサン等の非プロトン性溶媒中でアミノアセトアルデヒドジエチルアセタールと反応させる。工程(xi)から得られたアセタール(XIII)を次に室温又は通常の加熱もしくはマイクロ波加熱により50℃から120℃の温度にてアルコール(例えばエタノール、n−ブタノール、tert−ブタノール)や水等のプロトン性溶媒中でHCl(12N)等の強酸性条件を使用して環化し、イミダゾール(XIV)とした。 According to Scheme 2, in step (vii), potassium permanganate in the presence of a base such as pyridine in a protic solvent such as water at room temperature or a temperature of 50 to 100 ° C. by normal heating or microwave heating. The 2,4-dihalogenotoluene of formula (VIII) can be obtained by using a strong oxidizing agent such as, for example, or by other methods known to those skilled in the art, such as the method described in US Pat. No. 6,187,950. Oxidize to the corresponding acid derivative (IX). Alcohol (eg, ethanol, n-butanol, tert-butanol) or water at the 2-position of the acid (IX) obtained from step (vii) at room temperature or a temperature of 50 ° C. to 100 ° C. by normal heating or microwave heating Mono-substituted with an amine of formula R 4 —NH 2 where R 4 is as defined above for compounds of formula (I) in a protic solvent such as The acid (X) obtained from step (viii) is then carbonylated in an aprotic solvent such as DMF, toluene, THF, dioxane or the like at room temperature or at a temperature of 50 ° C. to 120 ° C. by normal heating or microwave heating. It is cyclized by the action of diimidazole or triphosgene to give benzo-1,3-oxazine-2,4-dione (XI). Next, benzo-1,3-oxazine-2,4-dione (XI) is added to DMF at room temperature in the presence of a base such as triethylamine or pyridine at a temperature of 50 ° C. to 120 ° C. by normal heating or microwave heating. Treatment with malononitrile in an aprotic solvent such as toluene, dioxane or other methods known to those skilled in the art, such as the method described in Synthesis (2008) 1535 by Iminov et al. Provides nitrile (XII). The nitrile (XII) obtained from the step (x) is DME, DMF, toluene, dioxane, etc. at room temperature or a temperature of 50 to 120 ° C. by ordinary heating or microwave heating in the presence of a copper catalyst such as CuCl. Is reacted with aminoacetaldehyde diethyl acetal in an aprotic solvent. The acetal (XIII) obtained from the step (xi) is then alcohol (eg ethanol, n-butanol, tert-butanol), water, etc. at room temperature or at a temperature of 50 ° C. to 120 ° C. by normal heating or microwave heating. Was cyclized into imidazole (XIV) using strongly acidic conditions such as HCl (12N) in a protic solvent.
本発明の式(I)の化合物を得るためには、式(VII)又は(XIV)のハロゲン化中間体から出発してスキーム3に示す2種類の方法を使用することができる。 To obtain the compounds of formula (I) of the present invention, two methods shown in Scheme 3 can be used starting from halogenated intermediates of formula (VII) or (XIV).
本発明の対象である式(I)の化合物を得るための第1の方法によると、工程(xiii)では、式(XVa)のプロパルギルアルコールR1R2CH(OR3)C≡CH(式中、R1、R2及びR3は上記に定義した通りである)の適切な誘導体との薗頭カップリング反応又は式(XVb)の適切なアリールボロン酸との鈴木カップリング反応で式(VII)又は(XIV)のハロゲン化中間体を使用する。薗頭反応(xiii)は例えばPd(PPh3)4、PdCl2(PPh3)2等の(酸化状態(0)又は(II)の)パラジウム錯体と、ヨウ化銅、トリエチルアミンの存在下、80から120℃の通常の加熱又はマイクロ波加熱下にてTHFやDMF等の非プロトン性極性溶媒中で実施される。 According to a first method for obtaining a compound of formula (I) which is the subject of the present invention, in step (xiii), propargyl alcohol R 1 R 2 CH (OR 3 ) C≡CH of formula (XVa) Wherein R 1 , R 2 and R 3 are as defined above) in a Sonogashira coupling reaction with a suitable derivative or a Suzuki coupling reaction with a suitable arylboronic acid of formula (XVb) VII) or (XIV) halogenated intermediates are used. Sonogashira reaction (xiii) is carried out in the presence of palladium complex (in oxidation state (0) or (II)) such as Pd (PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , copper iodide, triethylamine The reaction is carried out in an aprotic polar solvent such as THF and DMF under normal heating at 120 to 120 ° C. or microwave heating.
鈴木反応(xiii)は例えばPd(PPh3)4、PdCl2(PPh3)2、Pd2dba3、Xphos又はPdCl2(dppf)等の(酸化状態(0)又は(II)の)パラジウム錯体と、炭酸セシウム、炭酸水素ナトリウム水溶液又はK3PO4等の塩基の存在下、80から120℃の通常の加熱又は130から170℃のマイクロ波加熱下にてDME、エタノール、DMF、ジオキサン又はこれらの溶媒の混液等のプロトン性又は非プロトン性極性溶媒中で実施される。 Suzuki reaction (xiii) is a palladium complex (of oxidation state (0) or (II)) such as Pd (PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd 2 dba 3 , Xphos or PdCl 2 (dppf). And DME, ethanol, DMF, dioxane or these under normal heating at 80 to 120 ° C. or microwave heating at 130 to 170 ° C. in the presence of a base such as cesium carbonate, aqueous sodium hydrogen carbonate or K 3 PO 4 It is carried out in a protic or aprotic polar solvent such as a mixture of the above solvents.
薗頭(XVIa)又は鈴木(XVIb)反応生成物を最後に通常の脱保護工程(xiv)に従って例えばHCl(4N)等の酸のジオキサン又はトリフルオロ酢酸溶液の存在下、−5℃から60℃の温度にてエタノールやジクロロメタン等の溶媒中で脱保護し、式(I)の化合物を得る。 The Shantou (XVIa) or Suzuki (XVIb) reaction product is finally subjected to −5 ° C. to 60 ° C. in the presence of a dioxane or trifluoroacetic acid solution of an acid such as HCl (4N) according to the usual deprotection step (xiv) The compound of formula (I) is obtained by deprotection in a solvent such as ethanol or dichloromethane at the temperature of
本発明の対象である式(I)の化合物を得るための第2の方法によると、先ず工程(xiv)と同一の通常の手順に従い、式(VII)又は(XIV)のハロゲン化中間体を脱保護する(xv)。得られた無保護の化合物(XVII)を工程(xiii)について上述した条件と同一の条件に従い、プロパルギルアルコールR1R2CH(OR3)C≡CH(XVa)(式中、R1、R2及びR3は上記に定義した通りである)の適切な誘導体との薗頭カップリング反応又は式(XVb)の適切なアリールボロン酸との鈴木カップリング反応で使用する。どちらのカップリング反応でも化合物(I)が直接得られる。 According to the second method for obtaining the compound of formula (I) which is the subject of the present invention, first the halogenated intermediate of formula (VII) or (XIV) is prepared according to the same general procedure as in step (xiv). Deprotect (xv). The resulting unprotected compound (XVII) is treated with propargyl alcohol R 1 R 2 CH (OR 3 ) C≡CH (XVa) (wherein R 1 , R 1 ) according to the same conditions as described above for step (xiii) 2 and R 3 are as defined above) in a Sonogashira coupling reaction with a suitable derivative or a Suzuki coupling reaction with a suitable arylboronic acid of formula (XVb). Both coupling reactions give compound (I) directly.
必要に応じて、スキーム1に示す反応工程中に、R1、R2及びR3基上に存在するヒドロキシル基又は所定の反応性官能基を“Protective Groups in Organic Synthesis”,Greene et al.,2nd Edition(John Wiley & Sons,Inc.,New York)に記載されているように、当業者に公知の保護基で一時的に保護してもよい。 If necessary, during the reaction step shown in Scheme 1, hydroxyl groups or certain reactive functional groups present on the R 1 , R 2 and R 3 groups can be added to “Protective Groups in Organic Synthesis”, Greene et al. , 2nd Edition (John Wiley & Sons, Inc., New York), may be temporarily protected with a protecting group known to those skilled in the art.
別の態様によると、スキーム1に記載するような式(VII)の化合物も本発明の対象である。これらの化合物は式(I)の化合物の合成中間体として使用することができる。 According to another aspect, compounds of formula (VII) as described in Scheme 1 are also subject of the present invention. These compounds can be used as synthetic intermediates for compounds of formula (I).
別の態様によると、式(VII): According to another aspect, formula (VII):
又は一般式(XVb):
Or general formula (XVb):
式(VII)の化合物を一般式(XVa)の化合物又は一般式(XVb)の化合物と反応させる前又は後に通常の脱保護工程を実施することを特徴とする、式(I)の化合物の製造方法も本発明の対象である。
Preparation of a compound of formula (I), characterized in that a usual deprotection step is carried out before or after reacting a compound of formula (VII) with a compound of general formula (XVa) or a compound of general formula (XVb) The method is also the subject of the present invention.
以下の実施例では本発明の所定の化合物の製造について記載する。これらの実施例は限定的ではなく、本発明を例証するものに過ぎない。指定する化合物番号は表1に示す番号に相当する。得られた化合物の構造を微量元素分析、LC/MS分析及びIR又はNMRスペクトルにより確認する。 The following examples describe the preparation of certain compounds of the present invention. These examples are not limiting and merely illustrate the invention. The specified compound numbers correspond to the numbers shown in Table 1. The structure of the obtained compound is confirmed by trace element analysis, LC / MS analysis and IR or NMR spectrum.
実施例1:(化合物番号1)
2−アミノ−1−エチル−7−((3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]−ナフチリジン−4−オン
Example 1: (Compound No. 1)
2-Amino-1-ethyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8 ] -Naphthyridin-4-one
1.1:6−クロロ−2−エチルアミノニコチン酸
エチルアミンの溶液(70%水溶液)180mlに2,6−ジクロロニコチン酸18.0g(84.4mmol)を溶解した溶液を周囲温度にて72時間撹拌した。次に過剰のアミンを減圧蒸発させ、生成物が析出するまで10%酢酸水溶液を加えた。ベージュ色の固体をスピンフィルターで脱水し、冷水でリンスし、オーブン乾燥した。予想生成物10.5gが得られた。
融点=158−160℃。
収率=62%。
1.1: 6-chloro-2-ethylaminonicotinic acid A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml of a solution of ethylamine (70% aqueous solution) at ambient temperature for 72 hours Stir. The excess amine was then evaporated under reduced pressure and 10% aqueous acetic acid was added until the product precipitated. The beige solid was dehydrated with a spin filter, rinsed with cold water and oven dried. 10.5 g of the expected product is obtained.
Melting point = 158-160 ° C.
Yield = 62%.
1.2:6−クロロ−2−エチルアミノニコチノイルフルオリド
6−クロロ−2−エチルアミノニコチン酸5.0g(24.8mmol)をジクロロメタン125mlに懸濁した懸濁液にピリジン2ml(24.8mmol)と2,4,6−トリフルオロトリアジン4.2ml(49.8mmol)を加えた。混合物を周囲温度にて3時間撹拌後、濾過した。固体をジクロロメタン50mlでリンスし、濾液を氷冷水60mlで2回洗浄した。有機相をNa2SO4で乾燥し、溶媒を減圧蒸発させた。生成物5.01gがオレンジ色の油状物として得られ、それ以上精製せずに使用した。
収率=99%。
1.2: 6-Chloro-2-ethylaminonicotinoyl fluoride 6 ml of 6-chloro-2-ethylaminonicotinic acid (24.8 mmol) was suspended in 125 ml of dichloromethane in 2 ml of pyridine (24.24). 8 mmol) and 4.2 ml (49.8 mmol) of 2,4,6-trifluorotriazine were added. The mixture was stirred at ambient temperature for 3 hours and then filtered. The solid was rinsed with 50 ml of dichloromethane and the filtrate was washed twice with 60 ml of ice cold water. The organic phase was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure. 5.01 g of product was obtained as an orange oil and used without further purification.
Yield = 99%.
1.3:1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−カルボアルデヒド
水素化ナトリウム20.8gを鉱物油(50%,0.52mol)に懸濁した油性懸濁液を撹拌下にヘキサンで3回洗浄して鉱物油を洗い流し、DMF400mlに懸濁した。周囲温度にて撹拌下にイミダゾール−2−カルボアルデヒド50.0g(0.520mol)を懸濁液に加えた。1.5時間後に、2−(トリメチルシラニル)エトキシメチルクロリド101.0ml(0.572mol)を加え、反応混合物を更に1時間撹拌した。次に過剰の水を懸濁液に加え、反応混合物を酢酸エチルで3回抽出した。有機相をNa2SO4で乾燥し、溶媒を減圧蒸発させた。次に粗生成物をカラムクロマトグラフィー(DCM)により精製し、SEM保護イミダゾール−2−カルボアルデヒド85.0g(0.376mol)を得た。.
収率=72%。
MH+=227.1(C10H18N2O2Si,Mr=226.35)。
1H NMR(DMSO−d6,500MHz):δ9.83(s,1H);7.86(s,1H);7.39(s,1H);5.75(s,2H);3.58(t,2H);0.95(t,2H);0.02(s,9H)。
1.3: 1- (2-Trimethylsilanylethoxymethyl) -1H-imidazole-2-carbaldehyde An oily suspension obtained by suspending 20.8 g of sodium hydride in mineral oil (50%, 0.52 mol) The mineral oil was washed away with hexane three times under stirring, and suspended in 400 ml of DMF. Under stirring at ambient temperature, 50.0 g (0.520 mol) of imidazole-2-carbaldehyde was added to the suspension. After 1.5 hours, 101.0 ml (0.572 mol) of 2- (trimethylsilanyl) ethoxymethyl chloride was added and the reaction mixture was stirred for an additional hour. Excess water was then added to the suspension and the reaction mixture was extracted three times with ethyl acetate. The organic phase was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure. The crude product was then purified by column chromatography (DCM) to give 85.0 g (0.376 mol) of SEM protected imidazole-2-carbaldehyde. .
Yield = 72%.
MH + = 227.1 (C 10 H 18 N 2 O 2 Si, Mr = 226.35).
1H NMR (DMSO-d6,500 MHz): δ 9.83 (s, 1H); 7.86 (s, 1H); 7.39 (s, 1H); 5.75 (s, 2H); 3.58 ( t, 2H); 0.95 (t, 2H); 0.02 (s, 9H).
1.4:[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]アセトニトリル
トシルメチルイソシアニド1.73g(8.84mmol)をDME10mlに溶解し、−60℃まで冷却した。この温度で先ずカリウムtert−ブトキシド 1.98gを加えた後、1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−カルボアルデヒド2.00g(8.84mmol)をDME5mlに溶解した溶液をゆっくりと加えた。−60℃で2時間撹拌後に、反応混合物を0℃まで上げ、メタノール5ml(123.60mmol)を溶液に加えた。反応混合物を周囲温度にて更に24時間、40℃にて2時間撹拌した。過剰の水を加え、溶液をジクロロメタンで3回抽出した。有機相をNa2SO4で乾燥し、溶媒を減圧蒸発後、粗生成物を逆相カラムクロマトグラフィー(0.1%TFA水溶液/アセトニトリル=80/20)により精製し、SEM保護イミダゾール−アセトニトリル0.87g(0.367mol)を得た。
収率=41%。
MH+=238.1(C11H19N3OSi,Mr=237.38)。
1H NMR(DMSO−d6,500MHz):δ7.66(s,1H);7.39(s,1H);5.53(s,2H);4.52(s,2H);3.55(t,2H);0.92(t,2H);0.02(s,9H)。
1.4: [1- (2-Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] acetonitrile 1.73 g (8.84 mmol) of tosylmethyl isocyanide was dissolved in 10 ml of DME and cooled to −60 ° C. First, 1.98 g of potassium tert-butoxide was added at this temperature, and then 2.00 g (8.84 mmol) of 1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2-carbaldehyde was dissolved in 5 ml of DME. Was added slowly. After stirring at −60 ° C. for 2 hours, the reaction mixture was raised to 0 ° C. and 5 ml (123.60 mmol) of methanol was added to the solution. The reaction mixture was stirred at ambient temperature for a further 24 hours and at 40 ° C. for 2 hours. Excess water was added and the solution was extracted three times with dichloromethane. After drying the organic phase with Na 2 SO 4 and evaporating the solvent under reduced pressure, the crude product was purified by reverse phase column chromatography (0.1% aqueous TFA solution / acetonitrile = 80/20) and SEM protected imidazole-acetonitrile 0. Obtained .87 g (0.367 mol).
Yield = 41%.
MH + = 238.1 (C 11 H 19 N 3 OSi, Mr = 237.38).
1H NMR (DMSO-d6,500 MHz): δ 7.66 (s, 1H); 7.39 (s, 1H); 5.53 (s, 2H); 4.52 (s, 2H); 3.55 ( t, 2H); 0.92 (t, 2H); 0.02 (s, 9H).
1.5:3−(6−クロロ−2−エチルアミノピリジン−3−イル)−3−ヒドロキシ−2−[1−(2−(トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]アクリロニトリル
[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]アセトニトリル0.600g(2.53mmol)を無水THF10mlに溶解した0℃溶液にカリウムtert−ブチレート0.283g(2.53mmol)を少量ずつ加えた。混合物を周囲温度にて45分間撹拌後、再び0℃まで冷却した。次に6−クロロ−2−エチルアミノニコチノイルフルオリド0.512g(2.53mmol)をTHF10mlに溶解した溶液を加え、混合物を周囲温度にて一晩撹拌し、再び0℃まで冷却し、更にカリウムtert−ブチレート1当量(0.283g,2.53mmol)を加えた。周囲温度にて2時間撹拌後、飽和塩化アンモニウム水溶液50mlを加え、2N HClでpHを7に調整後、酢酸エチルで3回抽出した。有機相を合わせてMgSO4で乾燥し、溶媒を減圧蒸発させた。粗生成物をカラムクロマトグラフィー(DCM/メタノール=90:10)により更に精製し、標記化合物418mg(収率=38%)を中間体として得た後、次工程で使用した。
MH+=421(C19H26ClN5O2Si,Mr=419.99)。
1H NMR(DMSO−d6,500MHz):δ13.35(s,1H);7.70(d,1H);7.46(s,1H);7.23(s,1H);7.08(t,1H);6.58(d,1H);5.59(s,2H);3.58(t,2H);3.34(dq,2H);1.13(t,3H);−0.03(3s,9H)。
1.5: 3- (6-Chloro-2-ethylaminopyridin-3-yl) -3-hydroxy-2- [1- (2- (trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] Acrylonitrile [1- (2-Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] acetonitrile (0.600 g, 2.53 mmol) dissolved in anhydrous THF (10 ml) at 0 ° C. with 0.283 g of potassium tert-butylate (2 The mixture was stirred at ambient temperature for 45 minutes and then cooled again to 0 ° C. Next, 0.512 g (2.53 mmol) of 6-chloro-2-ethylaminonicotinoyl fluoride was added. A solution dissolved in 10 ml of THF is added and the mixture is stirred overnight at ambient temperature, cooled again to 0 ° C. 1 equivalent (0.283 g, 2.53 mmol) of tert-butylate was added, and after stirring at ambient temperature for 2 hours, 50 ml of saturated aqueous ammonium chloride solution was added, the pH was adjusted to 7 with 2N HCl, and then 3 with ethyl acetate. The combined organic phases were dried over MgSO 4 and the solvent was evaporated under reduced pressure The crude product was further purified by column chromatography (DCM / methanol = 90: 10) to give 418 mg of the title compound (Yield = 38%) as an intermediate and used in the next step.
MH + = 421 (C 19 H 26 ClN 5 O 2 Si, Mr = 419.99).
1H NMR (DMSO-d6,500 MHz): δ 13.35 (s, 1H); 7.70 (d, 1H); 7.46 (s, 1H); 7.23 (s, 1H); 7.08 ( 6.58 (d, 1H); 5.59 (s, 2H); 3.58 (t, 2H); 3.34 (dq, 2H); 1.13 (t, 3H); -0.03 (3s, 9H).
1.6:2−アミノ−7−クロロ−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン
1.5で製造した中間体3−(6−クロロ−2−エチルアミノピリジン−3−イル)−3−ヒドロキシ−2−[1−(2−(トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]アクリロニトリル418mg(1mmol)を無水THF5mlに溶解した0℃の低温溶液にカリウムtert−ブチレート0.112g(1mmol)を少量ずつ加えた。混合物を周囲温度にて48時間撹拌後、飽和塩化アンモニウム水溶液50mlを加え、2N HClでpHを7に調整し、反応混合物を酢酸エチルで3回抽出した。有機相を合わせてMgSO4で乾燥し、溶媒を減圧蒸発させ、標記化合物400mgを得た。
収率=38%。
MH+=421(C19H26ClN5O2Si,Mr=419.99)。
1H NMR(DMSO−d6,500MHz):δ8.50(d,1H);8.03(s,1H);7.98(s,1H);7.78(s,2H);7.60(s,1H);5.49(s,2H);4.58(q,2H);3.57(t,2H);1.42(t,3H);0.85(t,2H);−0.03(3s,9H)。
1.6: 2-amino-7-chloro-1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridine-4 Intermediate 3- (6-Chloro-2-ethylaminopyridin-3-yl) -3-hydroxy-2- [1- (2- (trimethylsilanylethoxymethyl) -1H- prepared in 1.5 0.112 g (1 mmol) of potassium tert-butyrate was added in small portions to a low temperature solution of 418 mg (1 mmol) of imidazol-2-yl] acrylonitrile in 5 ml of anhydrous THF at 0 ° C. After the mixture was stirred at ambient temperature for 48 hours, 50 ml of saturated aqueous ammonium chloride solution was added, the pH was adjusted to 7 with 2N HCl and the reaction mixture was extracted three times with ethyl acetate. Dried SO 4, the solvent is evaporated under reduced pressure to give the title compound 400 mg.
Yield = 38%.
MH + = 421 (C 19 H 26 ClN 5 O 2 Si, Mr = 419.99).
1H NMR (DMSO-d6,500 MHz): δ 8.50 (d, 1H); 8.03 (s, 1H); 7.98 (s, 1H); 7.78 (s, 2H); 7.60 ( 5.49 (s, 2H); 4.58 (q, 2H); 3.57 (t, 2H); 1.42 (t, 3H); 0.85 (t, 2H); -0.03 (3s, 9H).
1.7:(±)−2−メチルブタ−3−イン−1,2−ジオール
市販のエチニルマグネシウムクロリドの0.5Mテトラヒドロフラン溶液をテトラヒドロフラン200mlで希釈し、0℃まで冷却した。次にヒドロキアセトンをテトラヒドロフラン200mlに溶解した溶液を加え、混合物を周囲温度にて3時間撹拌した。反応混合物を冷却し、NH4Cl水溶液を加えた。混合物を酢酸エチルで3回抽出し、有機相を合わせて硫酸ナトリウムで乾燥し、濾過し、減圧(約200mbar)濃縮した。最終的に、予想生成物20gが茶色い油状物として得られ(定量的粗収率)、それ以上精製せずにラセミ体として使用したが、キラルHPLCカラムで分取HPLCにより純エナンチオマーに分離することもできた。光学的に純粋なエナンチオマーを得るためには、移動相として100barの圧力下で流速60ml/分にてCO2/2−プロパノール(70%/30%)又は流速120ml/分にてイソヘキサン/エタノール(70/30)混液+0.3%TFAを使用し、対応するラセミ混合物をキラル固定相(Chiralpak AD−Hカラム,250×21mm,5mm)で分取クロマトグラフィーに供した。
1.7: (±) -2-methylbut-3-in-1,2-diol A 0.5 M tetrahydrofuran solution of commercially available ethynylmagnesium chloride was diluted with 200 ml of tetrahydrofuran and cooled to 0 ° C. A solution of hydroxyacetone in 200 ml of tetrahydrofuran was then added and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was cooled and aqueous NH 4 Cl was added. The mixture was extracted three times with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure (ca. 200 mbar). Finally, 20 g of the expected product was obtained as a brown oil (quantitative crude yield), used as a racemate without further purification, but separated into pure enantiomers by preparative HPLC on a chiral HPLC column. I was able to. To obtain an optically pure enantiomer, the mobile phase is CO 2 / 2-propanol (70% / 30%) at a flow rate of 60 ml / min under a pressure of 100 bar or isohexane / ethanol (70% / min at a flow rate of 120 ml / min). The corresponding racemic mixture was subjected to preparative chromatography on a chiral stationary phase (Chiralpak AD-H column, 250 × 21 mm, 5 mm) using a 70/30) mixture + 0.3% TFA.
溶出と蒸発後に各エナンチオマーを単離し、各々の化学的純度とエナンチオマー純度を当業者に公知の分析法により測定した。 Each enantiomer was isolated after elution and evaporation and the chemical and enantiomeric purity of each was determined by analytical methods known to those skilled in the art.
1.8:2−アミノ−1−エチル−7−((3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン
アルゴン置換したマイクロ波反応フラスコに、2−アミノ−7−クロロ−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン500mg(1.2mmol)と、(3R)−1−メトキシ−2−メチルブタ−3−イン−2−オール204mg(1.8mmol)と、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド84mg(0.120mmol)と、ヨウ化銅(I)30mg(0.16mmol)と、DMF(脱気)2mlと、トリエチルアミン(脱気)2mlを仕込み、反応混合物を120℃に24時間維持するようにマイクロ波を照射した。溶媒を蒸発させ、固体をDMF3mlに再懸濁し、濾過した。次に濾液をHPLCにより精製し、標記化合物のTFA塩430mg(0.702mmol)を得た。
収率=59%。
MH+=498.2(C25H35N5O4Si,Mr=497.67)。
1H NMR(DMSO−d6,500MHz):δ8.39(d,1H);7.95(s,1H);7.88(s,1H);7.60(s,2H);7.48(d,1H);5.25(s,2H);4.50(ブロードシグナル,2H);3.52−3.40(ブロードシグナル,水ピーク+4H);1.48(s,3H);1.25(t,3H);−0.12(3s,9H)。
1.8: 2-Amino-1-ethyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one Into an argon-substituted microwave reaction flask was added 2-amino-7-chloro-1-ethyl-3- [1- (2 -Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one 500 mg (1.2 mmol) and (3R) -1-methoxy-2-methylbuta-3 -In-2-ol 204 mg (1.8 mmol), bis (triphenylphosphine) palladium (II) dichloride 84 mg (0.120 mmol), copper (I) iodide 30 m g (0.16 mmol), 2 ml of DMF (degassed) and 2 ml of triethylamine (degassed) were charged, and microwave irradiation was performed so that the reaction mixture was maintained at 120 ° C. for 24 hours. The solvent was evaporated and the solid was resuspended in 3 ml DMF and filtered. The filtrate was then purified by HPLC to give 430 mg (0.702 mmol) of the TFA salt of the title compound.
Yield = 59%.
MH + = 498.2 (C 25 H 35 N 5 O 4 Si, Mr = 497.67).
1H NMR (DMSO-d6,500 MHz): δ 8.39 (d, 1H); 7.95 (s, 1H); 7.88 (s, 1H); 7.60 (s, 2H); 7.48 ( d, 1H); 5.25 (s, 2H); 4.50 (broad signal, 2H); 3.52-3.40 (broad signal, water peak + 4H); 1.48 (s, 3H); 1 .25 (t, 3H); -0.12 (3 s, 9H).
1.9:2−アミノ−1−エチル−7−((3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
1.8のSEM保護ナフチリジンオン240mg(0.4mmol)を0℃にてTFA1.2mlとDCM1.2mlに溶解した。分析用HPLCがナフチリジンオンの完全な脱保護を示すまで、溶液を3から5℃に一晩維持した。過剰のNaHCO3水溶液を加えることにより溶液を中和した。次に混合物を酢酸エチルで3回抽出した。有機相を合わせてMgSO4で乾燥し、溶媒を減圧蒸発させた。こうして得られた粗生成物をシリカゲル(DCM:MeOH=4:1)で精製し、無保護の標記化合物143mg(定量的収率)を得た。
MH+=368.2(C19H21N5O3,Mr=367.41)。
1H NMR(DMSO−d6,500MHz):δ13.15(s,1H);11.55(bs,1H);8.59(d,1H);8.10(bs,1H);7.47(d,1H);7.25(s,1H);7.02(s,1H);5.85(s,1H);4.58(ブロードシグナル,2H);3.51−3.370(ブロードシグナル,水ピーク+4H);1.48(s,3H);1.25(t,3H)。
Rt(分析用HPLC):4.806分。
1.9: 2-amino-1-ethyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] Naphthyridin-4-one 1.8 SEM-protected naphthyridinone 240 mg (0.4 mmol) was dissolved in 1.2 ml TFA and 1.2 ml DCM at 0 ° C. The solution was maintained at 3-5 ° C. overnight until analytical HPLC showed complete deprotection of naphthyridinone. The solution was neutralized by adding excess aqueous NaHCO 3 solution. The mixture was then extracted 3 times with ethyl acetate. The organic phases were combined and dried over MgSO 4 and the solvent was evaporated under reduced pressure. The crude product thus obtained was purified on silica gel (DCM: MeOH = 4: 1) to give 143 mg (quantitative yield) of the unprotected title compound.
MH + = 368.2 (C 19 H 21 N 5 O 3, Mr = 367.41).
1H NMR (DMSO-d6,500 MHz): δ 13.15 (s, 1H); 11.55 (bs, 1H); 8.59 (d, 1H); 8.10 (bs, 1H); 7.47 ( d, 1H); 7.25 (s, 1H); 7.02 (s, 1H); 5.85 (s, 1H); 4.58 (broad signal, 2H); 3.51-3.370 ( Broad signal, water peak + 4H); 1.48 (s, 3H); 1.25 (t, 3H).
Rt (analytical HPLC): 4.806 min.
実施例2:(化合物番号2)
2−アミノ−1−プロピル−7−((3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
工程1.1でエチルアミンの代わりにn−プロピルアミンを使用し、工程1.6までに記載した手順を使用し、2−アミノ−7−クロロ−1−プロピル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オンを合成した。実施例1に概説した詳細な手順に従い、同様にこの中間体を(3R)−1−メトキシ−2−メチルブタ−3−イン−2−オールとカップリングし、標記化合物を得た。
MH+=382.48(C20H23N5O3,Mr=381.44)。
1H NMR(DMSO−d6,500MHz):δブロードシグナル:8.45(m,1H);7.4(m,3H);5.85(s,1H);4.58(m,3H);3.51−3.370(水ピーク+4H);1.70(m,2H);シャープなシグナル:1.48(s,3H);0.95(t,3H)。
Rt(分析用HPLC):4.98分。
Example 2: (Compound No. 2)
2-Amino-1-propyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8 Naphthyridin-4-one Using n-propylamine instead of ethylamine in step 1.1 and using the procedure described up to step 1.6, 2-amino-7-chloro-1-propyl-3- [1- (2-Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one was synthesized. This intermediate was similarly coupled with (3R) -1-methoxy-2-methylbut-3-in-2-ol following the detailed procedure outlined in Example 1 to give the title compound.
MH + = 382.48 (C 20 H 23 N 5 O 3, Mr = 381.44).
1H NMR (DMSO-d6,500 MHz): δ broad signal: 8.45 (m, 1H); 7.4 (m, 3H); 5.85 (s, 1H); 4.58 (m, 3H); 3.51-3.370 (water peak + 4H); 1.70 (m, 2H); sharp signal: 1.48 (s, 3H); 0.95 (t, 3H).
Rt (analytical HPLC): 4.98 min.
実施例3:(化合物番号3、27及び28)
2−アミノ−7−(3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
2−アミノ−7−((3R)−3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
2−アミノ−7−((3S)−3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
Example 3: (Compound Nos. 3, 27 and 28)
2-Amino-7- (3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 2-Amino-7-((3R) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridine-4 ( 1H) -one 2-amino-7-((3S) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8- Naphthyridine-4 (1H) -one
3.1:2−アミノ−1−エチル−7−(3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1,8−ナフチリジン−4(1H)−オン
1.6に記載した中間体(2−アミノ−7−クロロ−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル−1,8−ナフチリジン−4(1H)−オン)と、工程1.7に記載した手順に従って予め製造しておいた(±)−2−メチルブタ−3−イン−1,2−ジオールを使用し、工程1.8に概説した詳細な手順に従い、標記化合物を得た。
MH+=354.16(C18H19N5O3,Mr=353.38)。
Rt(分析用HPLC):4.48分。
3.1: 2-Amino-1-ethyl-7- (3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H -Imidazol-2-yl] -1,8-naphthyridin-4 (1H) -one Intermediates described in 1.6 (2-amino-7-chloro-1-ethyl-3- [1- (2-trimethyl) Silanylethoxymethyl) -1H-imidazol-2-yl-1,8-naphthyridin-4 (1H) -one) and (±) -2-2 previously prepared according to the procedure described in Step 1.7 The title compound was obtained using methylbut-3-yne-1,2-diol following the detailed procedure outlined in step 1.8.
MH + = 354.16 (C 18 H 19 N 5 O 3, Mr = 353.38).
Rt (analytical HPLC): 4.48 min.
3.2:2−アミノ−1−エチル−7−((3R)−3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1,8−ナフチリジン−4(1H)−オン
2−アミノ−1−エチル−7−((3S)−3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1,8−ナフチリジン−4(1H)−オン
工程3.1で得られたラセミ化合物をBerger分取SFC、230nmUV検出、固定相Chiralpak IC 20×250nm 5μm、移動相65%/35%CO2/(MeOH+0.5%イソプロピルアミン)、50ml/分、100barの条件下で分取Chiral SFC精製に供し、2種類のエナンチオマーに分離した。
3.2: 2-amino-1-ethyl-7-((3R) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- [1- (2-trimethylsilanylethoxy) Methyl) -1H-imidazol-2-yl] -1,8-naphthyridin-4 (1H) -one 2-amino-1-ethyl-7-((3S) -3,4-dihydroxy-3-methylbuta-1 -Inyl) -1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1,8-naphthyridin-4 (1H) -one obtained in step 3.1. The resulting racemate was obtained by Berger preparative SFC, 230 nm UV detection, stationary phase Chiralpak IC 20 × 250 nm 5 μm, mobile phase 65% / 35% CO 2 /(MeOH+0.5% isopropylamine), 50 l / min, subjected to preparative Chiral SFC purification under the conditions of 100 bar, was separated into two enantiomers.
2種類のエナンチオマーについて、Berger SFC、210nmUV検出、固定相Chiralpak AD−H(250mm×4.6)5μm、移動相65/35%CO2/(イソプロパノール+0.5%イソプロピルアミン)、2.4ml/分、100barの条件下でChiral SFC法を使用し、光学純度を分析した。
R体(tr=6.9分、エナンチオマー純度=97.9%)。
S体(tr=5.9分、エナンチオマー純度=96.8%)。
Berger SFC, 210 nm UV detection, stationary phase Chiralpak AD-H (250 mm × 4.6) 5 μm, mobile phase 65/35% CO 2 /(isopropanol+0.5% isopropylamine), 2.4 ml / min for the two enantiomers The optical purity was analyzed using the Chiral SFC method at 100 bar.
R-form (tr = 6.9 minutes, enantiomeric purity = 97.9%).
S form (tr = 5.9 minutes, enantiomeric purity = 96.8%).
3.3:2−アミノ−7−(3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
2−アミノ−7−((3R)−3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
2−アミノ−7−((3S)−3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
工程1.9に従う脱保護工程後に、化合物3、27及び28を黄色い粉末として単離した。
MH+=354.16(C18H19N5O3,Mr=353.38)。
Tr=0.77分。
1H NMR(DMSO−d6,400MHz):δ13.15(s,1H);11.55(bs,1H);8.55(d,1H,J=6.4Hz);8.10(bs,1H);7.47(d,1H,J=6.4Hz);7.15(s,1H);7.02(s,1H);5.6(s,1H);5.1(t,1H,J=6.4Hz)4.53(bd,2H);3.49(dd,1H,J=6.4;10.4Hz);3.41(dd,1H,J=6.4;10.4Hz)1.48(s,3H);1.27(t,3H,J=7.2Hz)。
3.3: 2-Amino-7- (3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridine-4 ( 1H) -one 2-amino-7-((3R) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8- Naphthyridin-4 (1H) -one 2-amino-7-((3S) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl)- 1,8-naphthyridin-4 (1H) -one After the deprotection step according to step 1.9, compounds 3, 27 and 28 were isolated as yellow powders.
MH + = 354.16 (C 18 H 19 N 5 O 3, Mr = 353.38).
Tr = 0.77 minutes.
1H NMR (DMSO-d6, 400 MHz): δ 13.15 (s, 1H); 11.55 (bs, 1H); 8.55 (d, 1H, J = 6.4 Hz); 8.10 (bs, 1H) 7.47 (d, 1H, J = 6.4 Hz); 7.15 (s, 1H); 7.02 (s, 1H); 5.6 (s, 1H); 5.1 (t, 1H, J = 6.4 Hz) 4.53 (bd, 2H); 3.49 (dd, 1H, J = 6.4; 10.4 Hz); 3.41 (dd, 1H, J = 6.4; 10.4 Hz) 1.48 (s, 3H); 1.27 (t, 3H, J = 7.2 Hz).
2種類のエナンチオマーについて、Berger SFC、230nmUV検出、固定相Chiralpak AD−H(250mm×4.6)5μm、移動相60/40%CO2/(イソプロパノール+0.5%イソプロピルアミン)、2.4ml/分、100barの条件下でChiral SFC法を使用し、光学純度を分析した。
R体(tr=8.37分、エナンチオマー純度=99.2%)。
S体(tr=7.29分、エナンチオマー純度=98.5%)。
For the two enantiomers, Berger SFC, 230 nm UV detection, stationary phase Chiralpak AD-H (250 mm × 4.6) 5 μm, mobile phase 60/40% CO 2 /(isopropanol+0.5% isopropylamine), 2.4 ml / min The optical purity was analyzed using the Chiral SFC method at 100 bar.
R-form (tr = 8.37 min, enantiomeric purity = 99.2%).
Form S (tr = 7.29 min, enantiomeric purity = 98.5%).
実施例4:(化合物番号4)
2−アミノ−1−エチル−7−(3−ヒドロキシ−3−ピリジン−2−イルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
1.6に記載した中間体(2−アミノ−7−クロロ−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン)を使用し、実施例1に概説した詳細な手順に従い、同様に(±)−2−ピリジン−2−イルブタ−3−イン−2−オールとカップリングし、標記化合物を得た。
MH+=401.21(C22H20N6O2,Mr=400.44)。
Rt(分析用HPLC):4.49分。
Example 4: (Compound No. 4)
2-Amino-1-ethyl-7- (3-hydroxy-3-pyridin-2-ylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine-4 -On Intermediates described in 1.6 (2-amino-7-chloro-1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [ 1,8] naphthyridin-4-one) and similarly coupled with (±) -2-pyridin-2-ylbut-3-in-2-ol according to the detailed procedure outlined in Example 1. To give the title compound.
MH + = 401.21 (C 22 H 20 N 6 O 2, Mr = 400.44).
Rt (analytical HPLC): 4.49 min.
実施例5:(化合物番号5)
2−アミノ−1−エチル−7−[(3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イン−1−イル]−3−(4−メチル−1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
5.1:4−メチル−1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−カルボアルデヒド
DMF73ml中で4(5)−メチル−1H−イミダゾール−2−カルボアルデヒド4g(36.3mmol)、水素化ナトリウム1.5g(38mmol)及び2−(トリメチルシラニル)エトキシメチルクロリド6.7g(40mmol)から出発し、実施例1の工程1.3と同一手順を使用し、標記化合物8.7gを茶色い油状物として得た(定量的収率)。
MH+=241(C11H20N2O2Si,240.377)。
Example 5: (Compound No. 5)
2-Amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-in-1-yl] -3- (4-methyl-1H-imidazol-2-yl) ) -1H- [1,8] naphthyridin-4-one 5.1: 4-Methyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2-carbaldehyde 4 (5)-in DMF 73 ml Example 1 starting from 4 g (36.3 mmol) of methyl-1H-imidazole-2-carbaldehyde, 1.5 g (38 mmol) of sodium hydride and 6.7 g (40 mmol) of 2- (trimethylsilanyl) ethoxymethyl chloride Using the same procedure as in step 1.3, 8.7 g of the title compound was obtained as a brown oil (quantitative yield).
MH + = 241 (C 11 H 20 N 2 O 2 Si, 240.377).
5.2:[4−メチル−1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]アセトニトリル
4−メチル−1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−カルボアルデヒド8.7g(32.7mmol)と、TOSMIC6.7g(34.3mmol)と、カリウムtert−ブチレート7.3g(65mmol)の無水DME(54ml)溶液から出発し、実施例1の工程1.4に記載した手順と同一手順を使用し、τ及びπの位置異性体の70/30混合物として黄色い油状物状の化合物6.6gを得た。
収率=80%。
MH+=252(C12H21N3OSi,251.404)。
Tr=6.38分及び6.55分。
5.2: [4-Methyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] acetonitrile 4-methyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole- Example 1 starting from a solution of 8.7 g (32.7 mmol) of 2-carbaldehyde, 6.7 g (34.3 mmol) of TOSMIC and 7.3 g (65 mmol) of potassium tert-butylate in anhydrous DME (54 ml). Using the same procedure as described in 1.4, 6.6 g of a yellow oily compound was obtained as a 70/30 mixture of τ and π regioisomers.
Yield = 80%.
MH + = 252 (C 12 H 21 N 3 OSi, 251.404).
Tr = 6.38 minutes and 6.55 minutes.
5.3:2−アミノ−7−クロロ−1−エチル−3−[4−メチル−1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン
工程6.2後に得られた化合物6.3g(25mmol)と、工程1.2後に得られた化合物5g(25mmol)と、カリウムtert−ブチレート7.2g(62mmol)の無水THF(83ml)溶液から出発し、実施例1の工程(1.5−1.6)に記載した手順と同一手順を使用し、τ及びπの2種類の異性体の80/20混合物としてベージュ色の粉末状の生成物4gを得、次工程で混合物のまま使用した。
収率=38%。
融点=120℃。
MH+=435(C20H28ClN5O2Si,434,013)。
Tr=10.5分及び10.6分。
両方の異性体の1H NMR(500MHz,DMSO−d6)δppm 8.45(d,J=8.07Hz,2H)7.70(b.s.,2H)7.56(b.s.,2H)7.43(d,J=8.07Hz,1H)7.42(d,J=8.07Hz,1H)6.99(m,1H)6.84(m,1H)5.18(s,2H)5.17(s,2H)4.43(q,J=6.85Hz,4H)3.19(m,2H)3.12(m,2H)2.25(d,J=0.98Hz,3H)2.16(d,J=0.98Hz,3H)1.24−1.29(m,6H)0.57−0.64(m,4H)−0.22(s,9H)−0.22(s,9H)。
5.3: 2-Amino-7-chloro-1-ethyl-3- [4-methyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8 ] Naphthyridin-4-one 6.3 g (25 mmol) of the compound obtained after step 6.2, 5 g (25 mmol) of the compound obtained after step 1.2, and 7.2 g (62 mmol) of potassium tert-butyrate anhydrous Beige as an 80/20 mixture of two isomers of τ and π, starting from a THF (83 ml) solution and using the same procedure as described in Example 1, steps (1.5-1.6) 4 g of a colored powder product was obtained and used as a mixture in the next step.
Yield = 38%.
Melting point = 120 ° C.
MH + = 435 (C 20 H 28 ClN 5 O 2 Si, 434,013).
Tr = 10.5 minutes and 10.6 minutes.
1H NMR of both isomers (500 MHz, DMSO-d6) δ ppm 8.45 (d, J = 8.07 Hz, 2H) 7.70 (bs, 2H) 7.56 (bs, 2H) 7.43 (d, J = 8.07 Hz, 1H) 7.42 (d, J = 8.07 Hz, 1H) 6.99 (m, 1H) 6.84 (m, 1H) 5.18 (s) , 2H) 5.17 (s, 2H) 4.43 (q, J = 6.85 Hz, 4H) 3.19 (m, 2H) 3.12 (m, 2H) 2.25 (d, J = 0 .98 Hz, 3H) 2.16 (d, J = 0.98 Hz, 3H) 1.24-1.29 (m, 6H) 0.57-0.64 (m, 4H) -0.22 (s, 9H) -0.22 (s, 9H).
5.4:2−アミノ−1−エチル−7−[(3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イン−1−イル]−3−[4−メチル−1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン
アルゴン置換したマイクロ波反応フラスコ内で、工程5.3後に得られた化合物0.5g(1.15mmol)と、(R)−1−メトキシ−2−メチルブタ−3−イン−2−オール0.26g(2.3mmol)と、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド40mg(0.06mmol)と、ヨウ化銅(I)22mg(0.12mmol)と、DMF(脱気)3mlと、トリエチルアミン(脱気)3mlを80℃に3時間加熱した。溶媒を蒸発させ、固体を酢酸エチルに溶解し、飽和NaHCO3水溶液とHCl(1N)で順次洗浄した。次に有機相をNa2SO4で乾燥し、濾過し、減圧濃縮した。次に残渣をシリカゲルフラッシュクロマトグラフィー(DCM/THF 95/5:MeOH(1%NH4OH)0%→10%)により精製し、標記化合物0.19gを得た。
収率:32%。
MH+=512(C26H37N5O4Si,511.695)。
1H NMR(400MHz,DMSO−d6)δppm 8.43(d,J=7.91Hz,2H)7.69(br.s.,2H)7.55(br.s.,2H)7.41(d,J=7.79Hz,2H)6.99(s,1H)6.84(s,1H)5.81(s,2H)5.18(s,4H)4.40−4.58(m,4H)3.47(d,J=9.54Hz,2H)3.37−3.43(m,8H)3.19(t,J=8.02Hz,2H)3.12(t,J=8.08Hz,2H)2.26(s,3H)2.17(s,3H)1.47(s,6H)1.26(t,J=6.57Hz,6H)0.54−0.67(m,4H)−0.23(s,18H)。
5.4: 2-Amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-in-1-yl] -3- [4-methyl-1- ( 2-Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one Compound 0 obtained after step 5.3 in an argon-substituted microwave reaction flask. 0.5 g (1.15 mmol), (R) -1-methoxy-2-methylbut-3-in-2-ol 0.26 g (2.3 mmol), and bis (triphenylphosphine) palladium (II) dichloride 40 mg (0.06 mmol), copper (I) iodide 22 mg (0.12 mmol), DMF (degassed) 3 ml, and triethylamine (degassed) 3 ml were heated to 80 ° C. for 3 hours. The solvent was evaporated and the solid was dissolved in ethyl acetate and washed sequentially with saturated aqueous NaHCO 3 and HCl (1N). The organic phase was then dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (DCM / THF 95/5: MeOH (1% NH 4 OH) 0% → 10%) to give 0.19 g of the title compound.
Yield: 32%.
MH + = 512 (C 26 H 37 N 5 O 4 Si, 511.695).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J = 7.91 Hz, 2H) 7.69 (br.s., 2H) 7.55 (br.s., 2H) 7.41 ( d, J = 7.79 Hz, 2H) 6.99 (s, 1H) 6.84 (s, 1H) 5.81 (s, 2H) 5.18 (s, 4H) 4.40-4.58 ( m, 4H) 3.47 (d, J = 9.54 Hz, 2H) 3.37-3.43 (m, 8H) 3.19 (t, J = 8.02 Hz, 2H) 3.12 (t, J = 8.08 Hz, 2H) 2.26 (s, 3H) 2.17 (s, 3H) 1.47 (s, 6H) 1.26 (t, J = 6.57 Hz, 6H) 0.54- 0.67 (m, 4H)-0.23 (s, 18H).
5.5:2−アミノ−1−エチル−7−[(3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イン−1−イル]−3−(4−メチル−1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
工程5.4後に得られた化合物0.18g(0.36mmol)を0℃でTFA1.7mlとDCM1.7mlに溶解した。溶液を3から5℃に一晩維持した。過剰のNaHCO3水溶液を加えることにより溶液を中和した。次に混合物を酢酸エチルで3回抽出した。有機相を合わせてNa2SO4で乾燥し、溶媒を減圧蒸発させた。粗生成物をDCM中で結晶化させることにより精製し、無保護の標記化合物62mg(収率46%)を得た。
MH+=382(C20H23N5O3,381.434)。
1H NMR(DMSO−d6,500MHz):(イミダゾール上の2種類の位相異性体が60/40比で検出された)δ=12.9−12.8(2s,1H)11.6(brs,1H)8.52(d,J=7.9Hz,1H)8.0(brs,1H)7.42(d,J=7.9Hz,1H)6.84−6.70(2s,1H)5.8(s,1H)4.56(m,2H)3.46(d,J=9.5Hz,1H)3.3(s,3H)3.4(d,J=9.5Hz,1H)2.28−2.2(2s 3H)1.47(s,3H)1.28(t,J=6.6Hz,3H)。
5.5: 2-Amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-in-1-yl] -3- (4-methyl-1H-imidazole) 2-yl) -1H- [1,8] naphthyridin-4-one 0.18 g (0.36 mmol) of the compound obtained after step 5.4 was dissolved in TFA 1.7 ml and DCM 1.7 ml at 0 ° C. The solution was maintained at 3-5 ° C. overnight. The solution was neutralized by adding excess aqueous NaHCO 3 solution. The mixture was then extracted 3 times with ethyl acetate. The organic phases were combined and dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure. The crude product was purified by crystallization in DCM to give 62 mg (46% yield) of the unprotected title compound.
MH + = 382 (C 20 H 23 N 5 O 3, 381.434).
1H NMR (DMSO-d6,500 MHz): (two phase isomers on imidazole were detected in 60/40 ratio) δ = 12.9-12.8 (2s, 1H) 11.6 (brs, 1H) 8.52 (d, J = 7.9 Hz, 1H) 8.0 (brs, 1H) 7.42 (d, J = 7.9 Hz, 1H) 6.84-6.70 (2s, 1H) 5.8 (s, 1H) 4.56 (m, 2H) 3.46 (d, J = 9.5 Hz, 1H) 3.3 (s, 3H) 3.4 (d, J = 9.5 Hz, 1H) 2.28-2.2 (2s 3H) 1.47 (s, 3H) 1.28 (t, J = 6.6 Hz, 3H).
実施例6:(化合物番号6)
2−アミノ−1−シクロプロピルメチル−7−(3−ヒドロキシペンタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
6.1:6−クロロ−2−(シクロプロピルメチルアミノ)ニコチン酸
密閉式管で、2,6−ジクロロニコチン酸3g(14mmol)のtert−ブタノール(14ml)溶液にシクロプロピルメチルアミン3g(42mmol)を加え、管を密閉し、Biotage Initiatorマイクロ波で170℃に30分間加熱した。反応混合物を室温まで冷却し、ジクロロメタン(100ml)で希釈し、10%酢酸水溶液(12ml)で洗浄した。有機相をNa2SO4で乾燥し、濾過し、濃縮し、減圧乾燥した。生成物3.4gをオレンジ色の油状物として得た。
定量的収率。
MH+=227。
Tr=4.54分。
Example 6: (Compound No. 6)
2-Amino-1-cyclopropylmethyl-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one 6.1 : 6-chloro-2- (cyclopropylmethylamino) nicotinic acid In a sealed tube, add 3 g (42 mmol) of cyclopropylmethylamine to a solution of 3 g (14 mmol) of 2,6-dichloronicotinic acid in tert-butanol (14 ml). The tube was sealed and heated in a Biotage Initiator microwave to 170 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane (100 ml) and washed with 10% aqueous acetic acid (12 ml). The organic phase was dried over Na 2 SO 4 , filtered, concentrated and dried under reduced pressure. 3.4 g of product was obtained as an orange oil.
Quantitative yield.
MH + = 227.
Tr = 4.54 minutes.
6.2:6−クロロ−2−(シクロプロピルメチルアミノ)ニコチノイルフルオリド
工程7.1後に得られた化合物0.334g(1.4mmol)をジクロロメタン4mlに溶解した溶液と、フッ化シアヌル0.38g(2.8mmol)と、トリエチルアミン0.28g(2.8mmol)から出発し、実施例1の工程1.2に記載した手順と同一手順を使用し、緑色の油状物として得られた生成物を精製せずに次工程で使用した。
6.2: 6-chloro-2- (cyclopropylmethylamino) nicotinoyl fluoride A solution obtained by dissolving 0.334 g (1.4 mmol) of the compound obtained after Step 7.1 in 4 ml of dichloromethane, and cyanuric fluoride 0 Starting from .38 g (2.8 mmol) and 0.28 g (2.8 mmol) of triethylamine, using the same procedure as described in step 1.2 of Example 1, the product obtained as a green oil The product was used in the next step without purification.
6.3:2−アミノ−7−クロロ−1−(シクロプロピルメチル)−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン
工程6.2後に得られた粗製化合物と、工程1.3後に得られた化合物0.32g(1.4mmol)を無水THF5mlに溶解した溶液と、カリウムtert−ブチレート0.4g(0.35mmol)から出発し、実施例1の工程(1.5−1.6)に記載した手順と同一手順を使用し、生成物0.56gを茶色い粉末として得た。
収率=90%。
融点=70℃。
MH+=447(C21H28ClN5O2Si)。
Tr=6.68分。
1H NMR(400MHz,DMSO−d6)δppm 8.46(d,J=8.05Hz,1H)7.67(br.s,2H)7.43(d,J=8.05Hz,1H)7.35(d,J=1.37Hz,1H)7.12(d,J=1.19Hz,1H)5.27(s,2H)4.38(d,J=7.04Hz,2H)3.19−3.25(m,2H)1.21−1.32(m,1H)0.59−0.68(m,2H)0.45−0.57(m,4H)−0.21(s,9H)。
6.3: 2-amino-7-chloro-1- (cyclopropylmethyl) -3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8 ] Naphthyridin-4-one A solution of the crude compound obtained after step 6.2, 0.32 g (1.4 mmol) of the compound obtained after step 1.3 in 5 ml of anhydrous THF, and potassium tert-butylate 0.8. Starting from 4 g (0.35 mmol), using the same procedure as described in Example 1 steps (1.5-1.6), 0.56 g of product was obtained as a brown powder.
Yield = 90%.
Melting point = 70 ° C.
MH + = 447 (C 21 H 28 ClN 5 O 2 Si).
Tr = 6.68 minutes.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (d, J = 8.05 Hz, 1H) 7.67 (br.s, 2H) 7.43 (d, J = 8.05 Hz, 1H) 35 (d, J = 1.37 Hz, 1H) 7.12 (d, J = 1.19 Hz, 1H) 5.27 (s, 2H) 4.38 (d, J = 7.04 Hz, 2H) 19-3.25 (m, 2H) 1.21-1.32 (m, 1H) 0.59-0.68 (m, 2H) 0.45-0.57 (m, 4H) -0.21 (S, 9H).
6.4:2−アミノ−1−(シクロプロピルメチル)−7−(3−ヒドロキシペンタ−1−イニル)−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン
工程6.3後に得られた化合物0.5g(1.2mmol)と、ペンタ−4−イン−3−オール0.22g(2.5mmol)と、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド43mg(0.06mmol)と、ヨウ化銅(I)23mg(0.12mmol)と、DMF(脱気)3mlと、トリエチルアミン(脱気)3mlから出発し、実施例5の工程5.4に記載した手順と同一手順を使用し、標記化合物0.19gを得た。
収率=30%。
MH+=494(C26H35N5O3Si,493.68)。
1H NMR(400MHz,DMSO−d6)δppm 8.44(d,J=7.87Hz,1H)7.65(br.s,2H)7.42(d,J=7.87Hz,1H)7.33(s,1H)7.10(s,1H)5.63(d,J=5.58Hz,1H)5.28(s,2H)4.38−4.52(m,3H)3.17−3.25(m,2H)1.67−1.76(m,2H)1.22−1.31(m,1H)1.01(t,J=7.36Hz,3H)0.59−0.66(m,2H)0.44−0.57(m,4H)−0.24−0.20(m,9H)。
6.4: 2-amino-1- (cyclopropylmethyl) -7- (3-hydroxypent-1-ynyl) -3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2- Yl] -1H- [1,8] naphthyridin-4-one 0.5 g (1.2 mmol) of the compound obtained after step 6.3, and 0.22 g (2.5 mmol) of penta-4-yne-3-ol. ), Bis (triphenylphosphine) palladium (II) dichloride 43 mg (0.06 mmol), copper (I) iodide 23 mg (0.12 mmol), DMF (degassed) 3 ml, triethylamine (degassed) 3 ml Using the same procedure as described in step 5.4 of Example 5, starting from, 0.19 g of the title compound was obtained.
Yield = 30%.
MH + = 494 (C 26 H 35 N 5 O 3 Si, 493.68).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J = 7.87 Hz, 1H) 7.65 (br.s, 2H) 7.42 (d, J = 7.87 Hz, 1H) 33 (s, 1H) 7.10 (s, 1H) 5.63 (d, J = 5.58 Hz, 1H) 5.28 (s, 2H) 4.38-4.52 (m, 3H) 17-3.25 (m, 2H) 1.67-1.76 (m, 2H) 1.22-1.31 (m, 1H) 1.01 (t, J = 7.36 Hz, 3H) 59-0.66 (m, 2H) 0.44-0.57 (m, 4H) -0.24-0.20 (m, 9H).
6.5:2−アミノ−1−シクロプロピルメチル−7−(3−ヒドロキシペンタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
工程7.4後に得られた化合物0.18g(0.36mmol)をTFA1.7mlとDCM1.7mlに溶解した溶液から出発し、実施例5の工程5.5に記載した手順と同一手順を使用し、標記化合物19mgを得た。
収率=15%。
融点=252℃。
MH+=364(C20H21N5O2,363.419)。
1H NMR(400MHz,DMSO−d6)δppm 13.15(br s,1H)11.5(br s,1H)8.56(d,J=7.9Hz,1H)8.0(br.s,1H)7.45(d,J=7.9Hz,1H)7.15(m,2H)5.62(br s,1H)4.62(m,2H+1H)1.75(m,2H)1.34(m,1H)1.05(t,J=7.36Hz,3H)0.5(m,2H)0.48−(m,2H)。
6.5: 2-amino-1-cyclopropylmethyl-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine-4- ON Starting from a solution of 0.18 g (0.36 mmol) of the compound obtained after step 7.4 in 1.7 ml of TFA and 1.7 ml of DCM, the same procedure as described in step 5.5 of example 5 is used. Used to give 19 mg of the title compound.
Yield = 15%.
Melting point = 252 ° C.
MH + = 364 (C 20 H 21 N 5 O 2, 363.419).
1H NMR (400 MHz, DMSO-d6) δ ppm 13.15 (br s, 1 H) 11.5 (br s, 1 H) 8.56 (d, J = 7.9 Hz, 1 H) 8.0 (br. S, 1H) 7.45 (d, J = 7.9 Hz, 1H) 7.15 (m, 2H) 5.62 (brs, 1H) 4.62 (m, 2H + 1H) 1.75 (m, 2H) 1 .34 (m, 1H) 1.05 (t, J = 7.36 Hz, 3H) 0.5 (m, 2H) 0.48- (m, 2H).
実施例7:(化合物番号7)
2−アミノ−1−エチル−7−((R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−キノリン−4−オン
7.1:2−フルオロ−4−ヨード安息香酸
2−フルオロ−4−ヨードトルエン5g(21.18mmol)とピリジン25.13g(317.77mmol)の水性懸濁液に過マンガン酸カリウム13.39g(84.74mmol)を加えた。混合物を加熱し、70℃で18時間撹拌した。反応が完了しなかったので、室温にて反応混合物に過マンガン酸カリウム3.34g(21.18mmol)を加え、混合物を70℃で更に6時間撹拌した。次に反応混合物をセライトパッドで濾過した後、水と酢酸エチルで洗浄した。デカント後、6N HCl水溶液を加えて水相をpH=1まで酸性化した。先ず白色固体を濾過し、水相を酢酸エチルで3回抽出した。有機相を合わせてMgSO4で乾燥し、溶媒を減圧蒸発させた。濾過した白色固体と酢酸エチルで抽出した固体を合計すると、4.1gが得られた。
収率=73%。
MH+=266.9(C7H4FIO2)。
1H NMR(DMSO−d6,400MHz):δ13.49(ブロードシグナル,1H);7.88(d,1H);7.78(d,1H);7.65(d,1H)。
Example 7: (Compound No. 7)
2-Amino-1-ethyl-7-((R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H-quinoline-4- 7.1: 2-Fluoro-4-iodobenzoic acid To an aqueous suspension of 2-fluoro-4-iodotoluene 5 g (21.18 mmol) and pyridine 25.13 g (317.77 mmol), potassium permanganate 13. 39 g (84.74 mmol) was added. The mixture was heated and stirred at 70 ° C. for 18 hours. Since the reaction was not complete, 3.34 g (21.18 mmol) of potassium permanganate was added to the reaction mixture at room temperature and the mixture was stirred at 70 ° C. for a further 6 hours. The reaction mixture was then filtered through a pad of celite and washed with water and ethyl acetate. After decanting, 6N aqueous HCl was added to acidify the aqueous phase to pH = 1. The white solid was first filtered and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and dried over MgSO 4 and the solvent was evaporated under reduced pressure. The filtered white solid and the solid extracted with ethyl acetate were combined to obtain 4.1 g.
Yield = 73%.
MH + = 266.9 (C 7 H 4 FIO 2).
1H NMR (DMSO-d6, 400 MHz): δ 13.49 (broad signal, 1H); 7.88 (d, 1H); 7.78 (d, 1H); 7.65 (d, 1H).
7.2:2−エチルアミノ−4−ヨード安息香酸
密閉した管内でエチルアミンの溶液(70%水溶液)16.11mlに2−フルオロ−4−ヨード安息香酸3.5g(13.16mmol)を混合した。反応容器を加熱し、125℃で24時間加熱した。反応混合物に窒素をバブリングし、過剰のエチルアミンを除去した。次に反応混合物を氷水に注ぎ、酢酸を加えて混合物をpH=3から4まで酸性化した。得られた白色固体を次に濾別し、水洗し、乾燥し、2.2g(7.55mmol)を得た。
収率=58%。
MH+=291.8(C9H10INO2)。
1H NMR(DMSO−d6,400MHz):δ12.5(br s,1H);7.55(d,1H);7.11(s,1H);6.9(d,1H)。
7.2: 2-ethylamino-4-iodobenzoic acid 3.5 g (13.16 mmol) of 2-fluoro-4-iodobenzoic acid was mixed with 16.11 ml of a solution of ethylamine (70% aqueous solution) in a sealed tube. . The reaction vessel was heated and heated at 125 ° C. for 24 hours. Nitrogen was bubbled through the reaction mixture to remove excess ethylamine. The reaction mixture was then poured into ice water and acetic acid was added to acidify the mixture from pH = 3-4. The resulting white solid was then filtered off, washed with water and dried to give 2.2 g (7.55 mmol).
Yield = 58%.
MH + = 291.8 (C 9 H 10 INO 2).
1H NMR (DMSO-d6, 400 MHz): δ 12.5 (brs, 1H); 7.55 (d, 1H); 7.11 (s, 1H); 6.9 (d, 1H).
7.3:1−エチル−7−ヨード−1H−ベンゾ[d][1,3]オキサジン−2,4−ジオン
2−エチルアミノ−4−ヨード安息香酸2.2g(7.55mmol)をジオキサン30mlに溶解した溶液に室温にてトリホスゲン0.785g(2.65mmol)を加えた。次に反応混合物を加熱し、110℃で2時間撹拌した。溶液を蒸発乾涸し、トルエン20mlを2回添加後に2回再蒸発させ、固体2.39g(7.5mmol)を得た。
収率=100%。
MH+=317.7(C10H8INO3)。
1H NMR(DMSO−d6,400MHz):δ7.87(s,1H);7.68(s,2H);4.04(m,2H);1.19(t,3H)。
7.3: 1-ethyl-7-iodo-1H-benzo [d] [1,3] oxazine-2,4-dione 2-ethylamino-4-iodobenzoic acid 2.2 g (7.55 mmol) was added to dioxane. To a solution dissolved in 30 ml, 0.785 g (2.65 mmol) of triphosgene was added at room temperature. The reaction mixture was then heated and stirred at 110 ° C. for 2 hours. The solution was evaporated to dryness and 20 ml of toluene was added twice and then re-evaporated twice to give 2.39 g (7.5 mmol) of solid.
Yield = 100%.
MH + = 317.7 (C 10 H 8 INO 3).
1H NMR (DMSO-d6, 400 MHz): δ 7.87 (s, 1H); 7.68 (s, 2H); 4.04 (m, 2H); 1.19 (t, 3H).
7.4:2−アミノ−1−エチル−7−ヨード−4−オキソ−1,4−ジヒドロキノリン−3−カルボニトリル
1−エチル−7−ヨード−1H−ベンゾ[d][1,3]オキサジン−2,4−ジオン2g(6.31mmol)をDMF25mLに溶解した溶液にマロノニトリル0.32g(6.31mmol)とトリエチルアミン1.45g(14.35mmol)を加えた。溶液を120℃で2時間撹拌し、トリエチルアミン0.73g(7.17mmol)の添加後、110℃で更に1時間撹拌した。次にDMFを減圧蒸発させ、残渣を水とジクロロメタンの混液に溶解した。この混合物を濾過し、予想化合物の第1の画分0.55g(1.62mmol)を得た。
収率=26%。
MH+=339.7(C10H8INO3)。
1H NMR(DMSO−d6,400MHz):δ7.99(s,1H);7.80(d,1H);7.7(m,2H);4.21(m,2H);1.20(t,3H)。
7.4: 2-Amino-1-ethyl-7-iodo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 1-ethyl-7-iodo-1H-benzo [d] [1,3] To a solution obtained by dissolving 2 g (6.31 mmol) of oxazine-2,4-dione in 25 mL of DMF, 0.32 g (6.31 mmol) of malononitrile and 1.45 g (14.35 mmol) of triethylamine were added. The solution was stirred at 120 ° C. for 2 hours, 0.73 g (7.17 mmol) of triethylamine was added, and further stirred at 110 ° C. for 1 hour. DMF was then evaporated under reduced pressure and the residue was dissolved in a mixture of water and dichloromethane. This mixture was filtered to give 0.55 g (1.62 mmol) of the first fraction of the expected compound.
Yield = 26%.
MH + = 339.7 (C 10 H 8 INO 3).
1H NMR (DMSO-d6, 400 MHz): δ 7.9 (s, 1H); 7.80 (d, 1H); 7.7 (m, 2H); 4.21 (m, 2H); 1.20 ( t, 3H).
7.5:2−アミノ−N−(2,2−ジエトキシエチル)−1−エチル−7−ヨード−4−オキソ−1,4−ジヒドロキノリン−3−カルボキサミジン
2−アミノ−1−エチル−7−ヨード−4−オキソ−1,4−ジヒドロキノリン−3−カルボニトリル0.48.g(1.43mmol)をDME 20mlに溶解した溶液にアミノアセトアルデヒドジエチルアセタール0.38g(2.86mmol)とCuCl 0.155g(1.57mmol)を加えた。溶液を撹拌し、100℃でマイクロ波を0.5時間照射した。
7.5: 2-Amino-N- (2,2-diethoxyethyl) -1-ethyl-7-iodo-4-oxo-1,4-dihydroquinoline-3-carboxamidine 2-amino-1-ethyl- 7-Iodo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 0.48. To a solution of g (1.43 mmol) dissolved in 20 ml of DME, 0.38 g (2.86 mmol) of aminoacetaldehyde diethyl acetal and 0.155 g (1.57 mmol) of CuCl were added. The solution was stirred and irradiated with microwaves at 100 ° C. for 0.5 hours.
次に溶液を濾別し、蒸発乾涸した。次に粗生成物をカラムクロマトグラフィー(DCM/MeOH:9/1)により精製し、固体0.57g(1.2mmol)を得た。
収率=78%。
MH+=473(C18H25IN4O3)。
The solution was then filtered off and evaporated to dryness. The crude product was then purified by column chromatography (DCM / MeOH: 9/1) to give 0.57 g (1.2 mmol) of a solid.
Yield = 78%.
MH + = 473 (C 18 H 25 IN 4 O 3).
7.6:2−アミノ−1−エチル−3−(1H−イミダゾール−2−イル)−7−ヨード−1H−キノリン−4−オン
2−アミノ−N−(2,2−ジエトキシエチル)−1−エチル−7−ヨード−4−オキソ−1,4−ジヒドロキノリン−3−カルボキサミジン0.13g(0.28mmol)の懸濁液に0℃にて12N HCl溶液0.37mlを加えた。反応混合物を室温にて16時間撹拌した。次に反応混合物を水0.55mlで希釈し、1N NaOH溶液0.32mlとNH4OH溶液0.134mlを加えて塩基性化した。次に混合物を濾過し、得られた固体を水、アセトニトリル及びペンタンで洗浄し、茶色い固体0.08g(0.21mmol)を得た。
収率=76%。
MH+=381(C14H13IN4O)。
7.6: 2-amino-1-ethyl-3- (1H-imidazol-2-yl) -7-iodo-1H-quinolin-4-one 2-amino-N- (2,2-diethoxyethyl) To a suspension of 0.13 g (0.28 mmol) of -1-ethyl-7-iodo-4-oxo-1,4-dihydroquinoline-3-carboxamidine, 0.37 ml of 12N HCl solution was added at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with 0.55 ml of water and basified by addition of 0.32 ml of 1N NaOH solution and 0.134 ml of NH 4 OH solution. The mixture was then filtered and the resulting solid was washed with water, acetonitrile and pentane to give 0.08 g (0.21 mmol) of a brown solid.
Yield = 76%.
MH + = 381 (C 14 H 13 IN 4 O).
7.7:2−アミノ−1−エチル−7−((R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−キノリン−4−オン
2−アミノ−1−エチル−3−(1H−イミダゾール−2−イル)−7−ヨード−1H−キノリン−4−オン0.43mg(1.15mmol)と、(R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イン0.262(23mmol)と、0.397g(3.45mmol)をDMF15ml中で混合した。この溶液にアルゴンを10分間バブリングした。1,1’−ビス(ジフェニルホスフィノ)フェロセンパラジウムジクロリド0.126mg(0.17mmol)とヨウ化銅0.033mg(0.17mmol)の添加後、反応混合物を80℃で6時間撹拌した。次に反応混合物を蒸発乾涸し、残渣をDCMと水の混液に注いだ。黒色不溶性固体を濾別した(100mg)。水相をジクロロメタンで3回抽出した。有機相を合わせてMgSO4で乾燥し、溶媒を減圧蒸発させた。次に残渣をカラムクロマトグラフィー(DCM/MeOH/NH4OH水溶液:9/1/0.1)により精製し、黄色い固体0.80g(1.2mmol)を得た。この固体をジクロロメタン中で再結晶させ、ベージュ色の固体0.02gを得た。
収率=4.5%。
MH+=367(C20H22N4O3,366.419)。
1H NMR(DMSO−d6,400MHz):δ13.19(s,1H);8.27(d,1H);7.61(s,1H);7.31(d,1H);7.13(s,1H);7.02(s,1H);6.94(ブロードシグナル,2H);4.36−4.28(ブロードシグナル,2H);3.45−3.25(ブロードシグナル,水ピーク+4H);1.46(s,3H);1.31(t,3H)。
7.7: 2-amino-1-ethyl-7-((R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- Quinolin-4-one 2-amino-1-ethyl-3- (1H-imidazol-2-yl) -7-iodo-1H-quinolin-4-one 0.43 mg (1.15 mmol) and (R)- 3-hydroxy-4-methoxy-3-methylbut-1-yne 0.262 (23 mmol) and 0.397 g (3.45 mmol) were mixed in 15 ml of DMF. This solution was bubbled with argon for 10 minutes. After the addition of 0.126 mg (0.17 mmol) of 1,1′-bis (diphenylphosphino) ferrocenepalladium dichloride and 0.033 mg (0.17 mmol) of copper iodide, the reaction mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was then evaporated to dryness and the residue was poured into a mixture of DCM and water. The black insoluble solid was filtered off (100 mg). The aqueous phase was extracted 3 times with dichloromethane. The organic phases were combined and dried over MgSO 4 and the solvent was evaporated under reduced pressure. Next, the residue was purified by column chromatography (DCM / MeOH / NH4OH aqueous solution: 9/1 / 0.1) to obtain 0.80 g (1.2 mmol) of a yellow solid. This solid was recrystallized in dichloromethane to give 0.02 g of a beige solid.
Yield = 4.5%.
MH + = 367 (C 20 H 22 N 4 O 3, 366.419).
1H NMR (DMSO-d6, 400 MHz): δ 13.19 (s, 1H); 8.27 (d, 1H); 7.61 (s, 1H); 7.31 (d, 1H); 7.13 ( 7.02 (s, 1H); 6.94 (broad signal, 2H); 4.36-4.28 (broad signal, 2H); 3.45-3.25 (broad signal, water) Peak + 4H); 1.46 (s, 3H); 1.31 (t, 3H).
実施例8:(化合物番号8)
2−アミノ−7−(3−クロロ−4−ヒドロキシフェニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
8.1:2−アミノ−7−(3−クロロ−4−ヒドロキシフェニル)−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン
丸底フラスコ内で2−アミノ−7−クロロ−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン0.3g(0.71mmol)と、3−クロロ−4−ヒドロキシフェニルボロン酸0.185g(1.07mmol)と、トリス(ジベンジリデンアセトン)ジパラジウム(0)0.098g(0.11mmol)と、トリシクロヘキシルホスフィン0.030mg(0.0.11mmol)と、リン酸三カリウム0.303gと、ジオキサン/水(50/50)(脱気)8mLを85℃で8時間加熱撹拌した。溶媒を蒸発させ、残渣をカラムクロマトグラフィー(DCM/MeOH:9/1)により精製し、茶色い固体0.4gを得た。この固体をそれ以上精製せずに次工程で使用した。
Example 8: (Compound No. 8)
2-Amino-7- (3-chloro-4-hydroxyphenyl) -1-ethyl-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one 8.1: 2 -Amino-7- (3-chloro-4-hydroxyphenyl) -1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8 ] Naphthyridin-4-one 2-Amino-7-chloro-1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [ 1,8] naphthyridin-4-one 0.3 g (0.71 mmol), 3-chloro-4-hydroxyphenylboronic acid 0.185 g (1.07 mmol), tris (dibenzylideneacetone) dipara Um (0) 0.098 g (0.11 mmol), tricyclohexylphosphine 0.030 mg (0.0.11 mmol), tripotassium phosphate 0.303 g, dioxane / water (50/50) (degassing) 8 mL was heated and stirred at 85 ° C. for 8 hours. The solvent was evaporated and the residue was purified by column chromatography (DCM / MeOH: 9/1) to give 0.4 g of a brown solid. This solid was used in the next step without further purification.
8.2:2−アミノ−7−(3−クロロ−4−ヒドロキシフェニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
粗製の2−アミノ−7−(3−クロロ−4−ヒドロキシフェニル)−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン400mg(0.59mmol)をDCM20mlに溶解した。0℃でTFA3.39gを加え、混合物を室温にて24時間撹拌した。過剰のNaHCO3水溶液を加えることにより溶液を中和した。次に混合物をDCMで3回抽出した。有機相を合わせてMgSO4で乾燥し、溶媒を減圧蒸発させた。こうして得られた粗生成物をシリカゲル(DCM:MeOH:NH4OH=4:10.1)で精製し、無保護の標記化合物0.035gを得た。
2工程の収率=13%。
MH+=382(C19H16ClN5O2,381.821)。
1H NMR(DMSO−d6,400MHz):δ13.19(s,1H);8.55(d,1H);8.2(s,1H);8.04(dd,1H);7.9(s,1H);7.15(s,1H);7.09(d,1H);7.3(s,1H);4.72−4.66(m,2H);1.37(t,3H)。
8.2: 2-amino-7- (3-chloro-4-hydroxyphenyl) -1-ethyl-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one Of 2-amino-7- (3-chloro-4-hydroxyphenyl) -1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1 , 8] naphthyridin-4-one 400 mg (0.59 mmol) was dissolved in 20 ml DCM. At 0 ° C., 3.39 g of TFA was added and the mixture was stirred at room temperature for 24 hours. The solution was neutralized by adding excess aqueous NaHCO 3 solution. The mixture was then extracted 3 times with DCM. The organic phases were combined and dried over MgSO 4 and the solvent was evaporated under reduced pressure. The crude product thus obtained was purified on silica gel (DCM: MeOH: NH 4 OH = 4: 10.1) to give 0.035 g of the unprotected title compound.
Yield of 2 steps = 13%.
MH + = 382 (C 19 H 16 ClN 5 O 2, 381.821).
1H NMR (DMSO-d6, 400 MHz): δ 13.19 (s, 1H); 8.55 (d, 1H); 8.2 (s, 1H); 8.04 (dd, 1H); 7.9 ( 7.15 (s, 1H); 7.09 (d, 1H); 7.3 (s, 1H); 4.72-4.66 (m, 2H); 1.37 (t , 3H).
実施例9:(化合物番号9)
2−アミノ−1−エチル−7−[3−(2−フルオロフェニル)−3−ヒドロキシブタ−1−イニル]−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
9.1:2−アミノ−1−エチル−7−クロロ−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
2−アミノ−7−クロロ−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン(1.0g,2.38mmol)をジクロロメタン30mLに溶解した。トリフルオロ酢酸30mLを加え、分析用HPLCから出発材料が完全に消費されたと判断されるまで、反応混合物を室温にて3時間撹拌した。溶媒を減圧除去し、残渣に酢酸エチルを加えた。溶液を飽和重炭酸ナトリウム水溶液で洗浄した。形成された沈殿を濾取した後、40℃で一晩減圧乾燥し、ベージュ色の粉末574mgを得た。
収率=83%。
1H NMR(DMSO−d6,600MHz):δ(ppm)13.09(s,1H);8.57(d,1H);7.47(d,1H);7.15(s,1H);7.03(s,1H);4.51(bq,2H);1.29(t,3H)。
Example 9: (Compound No. 9)
2-Amino-1-ethyl-7- [3- (2-fluorophenyl) -3-hydroxybut-1-ynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine -4-one 9.1: 2-amino-1-ethyl-7-chloro-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one 2-amino-7- Chloro-1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one (1.0 g, 2.38 mmol) ) Was dissolved in 30 mL of dichloromethane. 30 mL of trifluoroacetic acid was added and the reaction mixture was stirred at room temperature for 3 hours until analytical HPLC judged that the starting material was completely consumed. The solvent was removed under reduced pressure, and ethyl acetate was added to the residue. The solution was washed with saturated aqueous sodium bicarbonate. The formed precipitate was collected by filtration and dried under reduced pressure at 40 ° C. overnight to obtain 574 mg of a beige powder.
Yield = 83%.
1H NMR (DMSO-d6, 600 MHz): δ (ppm) 13.09 (s, 1H); 8.57 (d, 1H); 7.47 (d, 1H); 7.15 (s, 1H); 7.03 (s, 1H); 4.51 (bq, 2H); 1.29 (t, 3H).
9.2:2−アミノ−1−エチル−7−[3−(2−フルオロフェニル)−3−ヒドロキシブタ−1−イニル]−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン
ヨウ化銅(I)(23.7mg,0.12mmol)と、N−エチルモルホリン(130μL,1.04mmol)と、2−(2−フルオロフェニル)ブタ−3−イン−2−オール(76μL,0.52mmol)をDMF2.5mLに加えた。混合物をアルゴンで脱気した。[1,1’−ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)クロリドとジクロロメタンの1:1付加物(5.6mg,0.01mmol)と、中間体20.1(100mg,0.35mmol)を加えた。LCMSで残留している出発材料が認められなくなるまで、混合物をアルゴン雰囲気下で80℃にて2時間撹拌した。酢酸エチルを加えた。有機層を水、1N水酸化ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧蒸発させた。次に残渣をカラムクロマトグラフィー(DCM/MeOH/NH4OH水溶液:100/0/0→95/5/0.5)により精製し、オフホワイトの粉末30mgを得た。
収率=21%。
MH+=418。
Rt=0.57分(C23H20FN5O2,417.442)。
1H NMR(DMSO−d6,600MHz):δ13.10(bs,1H);8.54(d,1H);7.72(dt,1H);7.44(d,1H);7.38(m,1H);7.25−7.19(m,2H);7.13(d,1H);7.02(d,1H);6.62(s,1H);4.54(bq,2H);1.84(s,3H);1.27(t,3H)。
9.2: 2-Amino-1-ethyl-7- [3- (2-fluorophenyl) -3-hydroxybut-1-ynyl] -3- (1H-imidazol-2-yl) -1H- [1 , 8] naphthyridin-4-one copper (I) iodide (23.7 mg, 0.12 mmol), N-ethylmorpholine (130 μL, 1.04 mmol), 2- (2-fluorophenyl) but-3- In-2-ol (76 μL, 0.52 mmol) was added to 2.5 mL of DMF. The mixture was degassed with argon. [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) chloride and dichloromethane 1: 1 adduct (5.6 mg, 0.01 mmol) and intermediate 20.1 (100 mg, 0.35 mmol) Was added. The mixture was stirred at 80 ° C. for 2 hours under an argon atmosphere until no starting material remained by LCMS. Ethyl acetate was added. The organic layer was washed successively with water, 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was then purified by column chromatography (DCM / MeOH / NH 4 OH aqueous solution: 100/0/0 → 95/5 / 0.5) to obtain 30 mg of an off-white powder.
Yield = 21%.
MH + = 418.
Rt = 0.57 min (C 23 H 20 FN 5 O 2, 417.442).
1H NMR (DMSO-d6, 600 MHz): δ 13.10 (bs, 1H); 8.54 (d, 1H); 7.72 (dt, 1H); 7.44 (d, 1H); 7.38 ( m, 1H); 7.25-7.19 (m, 2H); 7.13 (d, 1H); 7.02 (d, 1H); 6.62 (s, 1H); 4.54 (bq) , 2H); 1.84 (s, 3H); 1.27 (t, 3H).
実施例10:(化合物番号12)
2−アミノ−7−(3−ヒドロキシペンタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1−(2−メトキシエチル)−1H−[1,8]ナフチリジン−4−オン
シクロプロピルメチルアミンの代わりに2−メトキシエタンアミンから工程1を出発し、実施例6の工程1及び2に記載した手順と同様の手順に従った後、2−(2−フルオロフェニル)ブタ−3−イン−2−オールの代わりにペンタ−1−イン−3−オールから出発し、実施例20の工程2と同一手順に従い、生成物15mgを粉末として得た。
MH+=368。
Rt=0.46分(C19H21N5O3 367,407)。
Example 10: (Compound No. 12)
2-Amino-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1- (2-methoxyethyl) -1H- [1,8] naphthyridin-4-one Starting from step 1 with 2-methoxyethanamine instead of cyclopropylmethylamine and following a procedure similar to that described in steps 1 and 2 of Example 6, 2- (2-fluorophenyl) buta- Starting from penta-1-in-3-ol instead of 3-in-2-ol, following the same procedure as step 2 of Example 20, 15 mg of product was obtained as a powder.
MH + = 368.
Rt = 0.46 min (C 19 H 21 N 5 O 3 367,407).
実施例11:(化合物番号19)
2−アミノ−1−エチル−3−(1H−イミダゾール−2−イル)−7−(4,4,4−トリフルオロ−3−ヒドロキシ−3−フェニルブタ−1−イニル)−1H−[1,8]ナフチリジン−4−オン
11.1:2−アミノ−1−エチル−7−(4,4,4−トリフルオロ−3−ヒドロキシ−3−フェニルブタ−1−イニル)−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン
2−アミノ−7−クロロ−1−エチル−3−[1−(2−トリメチルシラニルエトキシメチル)−1H−イミダゾール−2−イル]−1H−[1,8]ナフチリジン−4−オン0.4g(0.95mmol)と、1,1,1−トリフルオロ−2−フェニルブタ−3−イン−2−オール0.4g(1.9mmol)、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド33mg(0.05mmol)と、ヨウ化銅(I)18mg(0.1mmol)と、DMF(脱気)3mlと、トリエチルアミン(脱気)3mlから出発し、実施例5の工程5.4に記載した手順と同一手順を使用し、標記化合物0.15gを得た。
収率=30%。
MH+=584(C29H32N5O3Si)。
1H NMR(250MHz,DMSO−d6)δppm 8.52(d,J=7.91Hz,1H)8.21(s,1H)7.76−7.84(m,2H)7.72(br.s,2H)7.64(d,J=7.91Hz,1H)7.46−7.57(m,3H)7.33(d,J=1.34Hz,1H)7.10(d,J=1.34Hz,1H)5.28(s,2H)4.44−4.57(m,2H)3.16−3.27(m,2H)1.28(t,J=6.91Hz,3H)0.57−0.69(m,2H)−0.22(s,9H)。
Example 11: (Compound No. 19)
2-Amino-1-ethyl-3- (1H-imidazol-2-yl) -7- (4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-ynyl) -1H- [1 , 8] naphthyridin-4-one 11.1: 2-amino-1-ethyl-7- (4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-ynyl) -3- [1 -(2-Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one 2-amino-7-chloro-1-ethyl-3- [1- ( 2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one 0.4 g (0.95 mmol) and 1,1,1-trifluoro-2 -Phenylbut-3-yne-2- 0.4 g (1.9 mmol), bis (triphenylphosphine) palladium (II) dichloride 33 mg (0.05 mmol), copper (I) iodide 18 mg (0.1 mmol), DMF (degassed) 3 ml And using the same procedure as described in step 5.4 of Example 5, starting from 3 ml of triethylamine (degassed) gave 0.15 g of the title compound.
Yield = 30%.
MH + = 584 (C 29 H 32 N 5 O 3 Si).
1H NMR (250 MHz, DMSO-d6) δ ppm 8.52 (d, J = 7.91 Hz, 1H) 8.21 (s, 1H) 7.76-7.84 (m, 2H) 7.72 (br. s, 2H) 7.64 (d, J = 7.91 Hz, 1H) 7.46-7.57 (m, 3H) 7.33 (d, J = 1.34 Hz, 1H) 7.10 (d, J = 1.34 Hz, 1H) 5.28 (s, 2H) 4.44-4.57 (m, 2H) 3.16-3.27 (m, 2H) 1.28 (t, J = 6. 91 Hz, 3H) 0.57-0.69 (m, 2H) -0.22 (s, 9H).
11.2:2−アミノ−1−エチル−3−(1H−イミダゾール−2−イル)−7−(4,4,4−トリフルオロ−3−ヒドロキシ−3−フェニルブタ−1−イニル)−1H−[1,8]ナフチリジン−4−オン
TFA1.2mlとDCM1.2ml中で工程21.1後に得られた化合物0.145g(0.25mmol)から出発し、、実施例5の工程5.5に記載した手順と同一手順を使用し、標記化合物97mgを得た。
収率=86%。
融点=260℃。
MH+=454(C23H18F3N5O2)。
Rt=7.29分。
1H NMR(400MHz,DMSO−d6),δppm 13.12(br.s.,1H)11.58(br.s.,1H)8.63(d,J=7.87Hz,1H)8.21(s,1H)8.19(br.s,1H)7.77−7.82(m,2H)7.66(d,J=7.87Hz,1H)7.46−7.55(m,3H)7.14(br.s.,2H)4.57(q,J=6.59Hz,2H)1.30(t,J=7.00Hz,3H)。
11.2: 2-amino-1-ethyl-3- (1H-imidazol-2-yl) -7- (4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-ynyl)- 1H- [1,8] naphthyridin-4-one Starting with 0.145 g (0.25 mmol) of the compound obtained after step 21.1 in 1.2 ml TFA and 1.2 ml DCM, step 5. Using the same procedure described in 5, 5 mg of the title compound was obtained.
Yield = 86%.
Melting point = 260 ° C.
MH + = 454 (C 23 H 18 F 3 N 5 O 2).
Rt = 7.29 min.
1H NMR (400 MHz, DMSO-d6), δ ppm 13.12 (br.s., 1H) 11.58 (br.s., 1H) 8.63 (d, J = 7.87 Hz, 1H) 8.21 (S, 1H) 8.19 (br. S, 1H) 7.77-7.82 (m, 2H) 7.66 (d, J = 7.87 Hz, 1H) 7.46-7.55 (m , 3H) 7.14 (br.s., 2H) 4.57 (q, J = 6.59 Hz, 2H) 1.30 (t, J = 7.00 Hz, 3H).
化合物10及び11は実施例6に記載した手順と同様の手順で製造した。 Compounds 10 and 11 were prepared by procedures similar to those described in Example 6.
化合物13、14、15、16、17、18、20、21、25は実施例10に記載した手順と同様の手順で製造した。 Compounds 13, 14, 15, 16, 17, 18, 20, 21, 25 were prepared by procedures similar to those described in Example 10.
化合物22、23及び24は実施例11に記載した手順と同様の手順で製造した。 Compounds 22, 23 and 24 were prepared by a procedure similar to that described in Example 11.
化合物29は実施例1に記載した手順と同様の手順で製造した。 Compound 29 was prepared by a procedure similar to that described in Example 1.
実施例5及び6で使用した装置
マイクロ波装置:Biotage,initiator
Apparatus used in Examples 5 and 6 Microwave apparatus: Biotage, initiator
分析法LC/UV/MS保持時間(Rt)検出
化合物1、2、3及び4(Rt)を分析するために使用したLC/UV/MS分析法:
カラム:Merk Chromolith performance RP18e,100×4.6mm,3.5μm
溶媒A:H2O/TFA(99.9/0.1)
溶媒B:ACN/TFA(99.9/0.1)
流速:2ml/分
グラジエント(A/B):98/2(0分)→0/100(8分)→98/2(10分)
検出:254.16nm。
Analytical Method LC / UV / MS Retention Time (Rt) Detection LC / UV / MS analytical method used to analyze compounds 1, 2, 3 and 4 (Rt):
Column: Merk Chromolis performance RP18e, 100 × 4.6 mm, 3.5 μm
Solvent A: H 2 O / TFA (99.9 / 0.1)
Solvent B: ACN / TFA (99.9 / 0.1)
Flow rate: 2 ml / min Gradient (A / B): 98/2 (0 min) → 0/100 (8 min) → 98/2 (10 min)
Detection: 254.16 nm.
化合物9、12、13、14、17、18及び20(Rt)を分析するために使用したLC/UV/MS分析法:
UPLC SQDエレクトロスプレーイオン化、正イオンモード(30V)
カラム:Ascentis Express 50×2.1mm 2.7μm、T=55℃
溶媒A:H2O+0.02%TFA
溶媒B:CH3CN+0.014%TFA
流速:1mL/分
グラジエント(A/B v/v):98/2(t=0分),2/98(t=1分),2/98(t=1.3分),98/2(t=1.33分),次の注入(t=1.5分)
検出:220nm。
LC / UV / MS analytical method used to analyze compounds 9, 12, 13, 14, 17, 18 and 20 (Rt):
UPLC SQD electrospray ionization, positive ion mode (30V)
Column: Ascentis Express 50 × 2.1 mm 2.7 μm, T = 55 ° C.
Solvent A: H 2 O + 0.02% TFA
Solvent B: CH 3 CN + 0.014% TFA
Flow rate: 1 mL / min gradient (A / B v / v): 98/2 (t = 0 min), 2/98 (t = 1 min), 2/98 (t = 1.3 min), 98/2 (T = 1.33 minutes), next injection (t = 1.5 minutes)
Detection: 220 nm.
化合物5、6、10、11、19、22、23及び24を分析するために使用した分析法:
HPLCシステム:1100シリーズ質量分析計MSD SL(Agilent)
ソフトウェア:Agilent製品Chemstation version B.01.03
イオン化モード:エレクトロスプレー正イオンモードESI+
質量範囲:90〜1500uma
カラム:Symmetry C18 3.5μm(2.1×50mm)(Waters)T=25℃,pH:3
溶離液A:H2O+0.005%TFA
B:CH3CN+0.005%TFA
流速:0.4ml/分
グラジエント:0→10分0→100%B及び10→15分100B%
検出:220nm。
Analytical methods used to analyze compounds 5, 6, 10, 11, 19, 22, 23 and 24:
HPLC system: 1100 series mass spectrometer MSD SL (Agilent)
Software: Agilent product Chemstation version 01.03
Ionization mode: Electrospray positive ion mode ESI +
Mass range: 90-1500uma
Column: Symmetry C18 3.5 μm (2.1 × 50 mm) (Waters) T = 25 ° C., pH: 3
Eluent A: H 2 O + 0.005% TFA
B: CH 3 CN + 0.005% TFA
Flow rate: 0.4 ml / min Gradient: 0 → 10 minutes 0 → 100% B and 10 → 15 minutes 100 B%
Detection: 220 nm.
化合物7、8、15、16、21、25、26(Rt)に使用したLC/UV/MS分析法:
UPLC LCTエレクトロスプレーイオン化、正イオンモード(15V,30V)
ソフトウェア:Masslyx V4.1
カラム:Acquity UPLC BEH C1850×2.1mm 2.7μm,T=40℃
溶媒A:H2O+0.05%TFA
溶媒B:CH3CN+0.035%TFA
流速:1mL/分
グラジエント(A/Bv/v):98/2(t=0分),0/100(t=1.6分),0/100(t=2.1分),98/2(t=2.5分),次の注入(t=3分)
検出:220nm。
LC / UV / MS analysis method used for compounds 7, 8, 15, 16, 21, 25, 26 (Rt):
UPLC LCT electrospray ionization, positive ion mode (15V, 30V)
Software: Masslyx V4.1
Column: Acquity UPLC BEH C1850 × 2.1 mm 2.7 μm, T = 40 ° C.
Solvent A: H 2 O + 0.05% TFA
Solvent B: CH 3 CN + 0.035% TFA
Flow rate: 1 mL / min Gradient (A / Bv / v): 98/2 (t = 0 min), 0/100 (t = 1.6 min), 0/100 (t = 2.1 min), 98 / 2 (t = 2.5 minutes), next injection (t = 3 minutes)
Detection: 220 nm.
NMR
DMSO−d5のピークを内部標準とし、DMSO−d6中でNMR分光計Bruker 250、300、400又は600MHzを使用して1H NMRスペクトルを得た。化学シフトδは百万分率(ppm)で表記する。
NMR
Using the DMSO-d5 peak as an internal standard, a 1H NMR spectrum was obtained using an NMR spectrometer Bruker 250, 300, 400 or 600 MHz in DMSO-d6. The chemical shift δ is expressed in parts per million (ppm).
観測されたシグナルは次のように表記する:s=一重線;d=二重線;t=三重線;q=四重線;m=多重線又は線幅の広い一重線;br=ブロード;H=陽子。 The observed signal is expressed as: s = single line; d = double line; t = triple line; q = quadruple line; m = multiple line or wide single line; br = broad; H = proton.
融点
260℃未満の融点はコフラーベンチで測定し、260℃を上回る融点はBuchi B−545計器を使用して測定した。
Melting points Melting points below 260 ° C were measured with a Kofler bench, and melting points above 260 ° C were measured using a Buchi B-545 instrument.
旋光能
旋光能はPolarimeter Perkin−Elmer,供給電流55μAの型の旋光計で測定した。
Optical rotation power was measured with a polarimeter Perkin-Elmer, a polarimeter with a supply current of 55 μA.
本発明の化合物を薬理アッセイに供し、VEGFR−3の自己リン酸化に及ぼすその阻害効果を測定すると共に、下記アッセイに記載するようにそのex vivo活性を評価した。 The compounds of the present invention were subjected to a pharmacological assay to determine their inhibitory effect on autophosphorylation of VEGFR-3 and to evaluate its ex vivo activity as described in the assay below.
HEK細胞内のVEGFR−3自己リン酸化に及ぼす化合物の効果
HEK細胞内のVEGFR−3の過剰発現後にVEGFR−3自己リン酸化の阻害における化合物の効果をELISAにより定量した。10%ウシ胎仔血清(FCS)とグルタミンを添加したMEMにHEK293T細胞を維持した。トランスフェクションの前日に、48ウェルプレートにウェル当たり細胞104個を撒き、Fugene−6(Roche,Basel)を使用してトランスフェクションを行った。Fugene−6(18μL)にoptimem282μlを加えて5分間プレインキュベートした。次にVFGR−3−Flagに対応するDNA3μgを加え、室温にて10分間放置した後、200μlをHEK細胞上に分配した。24時間後に培地を捨て、新鮮な無血清培地に交換し、各種濃度(3から1000nM)の各化合物を加えて1時間インキュベートした。オルトバナデート(0.4mM)を加えて更に30分間インキュベーション後、オルトバナデートを添加した冷PBSで細胞を洗浄した後、RIPAバッファー300μlで溶解させた。次に溶解液を10000gで10分間遠心した。抗Flagをプレコートした96ウェルプレート2枚に上清(75μl)を分配し、室温にて1時間放置した。0.5%tween20を添加したTBSバッファーで3回洗浄後、HRPに共役させた抗ホスホチロシンを加え、室温にて1時間インキュベートした。その後、tween 20(0.5%)とMgCl2(2mM)を添加したTBSバッファーでウェルを3回洗浄した。H2SO4(2N)50μlを加えて反応を停止させ、Envisionで485及び530のシグナルを読取った。
Effect of compounds on VEGFR-3 autophosphorylation in HEK cells The effect of compounds on inhibition of VEGFR-3 autophosphorylation after overexpression of VEGFR-3 in HEK cells was quantified by ELISA. HEK293T cells were maintained in MEM supplemented with 10% fetal calf serum (FCS) and glutamine. The day before transfection, 104 cells were seeded per well in a 48-well plate, and transfection was performed using Fugene-6 (Roche, Basel). To Fugene-6 (18 μL), 282 μl of optimem was added and preincubated for 5 minutes. Next, 3 μg of DNA corresponding to VFGR-3-Flag was added and allowed to stand at room temperature for 10 minutes, and then 200 μl was distributed on HEK cells. After 24 hours, the medium was discarded and replaced with fresh serum-free medium, and each compound at various concentrations (3 to 1000 nM) was added and incubated for 1 hour. Orthovanadate (0.4 mM) was added and further incubated for 30 minutes, and then the cells were washed with cold PBS supplemented with orthovanadate and then lysed with 300 μl of RIPA buffer. The lysate was then centrifuged at 10,000g for 10 minutes. The supernatant (75 μl) was distributed to two 96-well plates pre-coated with anti-Flag and left at room temperature for 1 hour. After washing 3 times with TBS buffer supplemented with 0.5% tween 20, anti-phosphotyrosine conjugated to HRP was added and incubated at room temperature for 1 hour. Thereafter, the wells were washed three times with TBS buffer supplemented with tween 20 (0.5%) and MgCl 2 (2 mM). The reaction was stopped by adding 50 μl of H 2 SO 4 (2N), and the signals at 485 and 530 were read with Envision.
Ratkovsky and Reedy(Ratkovsky DA.,Reedy TJ.Choosing near−linear parameters in the four parameters logistic model radioligands and related assays.Biometrics 1986 Sep 42(3):575−82.)による4パラメータロジスティックモデルを使用して当社ソフトウェアBiost@t−SPEED v2.0で濃度反応曲線を解析した。 Ratkovsky and Reedy (Ratkovsky DA., Reedy TJ. Choosing near-linear parameters in the four parameters logistic ss. Concentration response curves were analyzed with the software Biost @ t-SPEED v2.0.
本発明の化合物はVEGFR−3の自己リン酸化に対する阻害活性をもち、HEK細胞内の自己リン酸化で1μM未満、特に1から500nM、より特定的には1から100nMのIC50値を示す。 The compounds of the present invention have inhibitory activity against autophosphorylation of VEGFR-3 and show IC 50 values of less than 1 μM, especially 1 to 500 nM, more particularly 1 to 100 nM, in autophosphorylation in HEK cells.
例として、表1の化合物のIC50値を下表2に示す。 As an example, the IC 50 values for the compounds in Table 1 are shown in Table 2 below.
本発明によるVEGFR−3チロシンキナーゼの阻害剤はVEGFR3の自己リン酸化の阻害を測定するアッセイを使用した場合に良好なex vivo活性を示し、従来技術の阻害剤の1種よりも良好である。 Inhibitors of VEGFR-3 tyrosine kinase according to the present invention show good ex vivo activity when using an assay that measures inhibition of autophosphorylation of VEGFR3 and are better than one of the prior art inhibitors.
Ex vivoアッセイ
マウスへの製剤投与プロトコール:
乳鉢で十分な量の最終容量となるように0.5%Tween 80と0.6%メチルセルロースを加えて製剤を調製する。8から15週齢雄性Balb/cマウスに強制飼養(10ml/kg)により懸濁液を投与する。30mg/kgの単回経口投与から3時間後又は6時間後に動物にペントバルビタールを投与して麻酔し、大静脈から血液サンプル(400μL)を採取し、ヘパリンリチウム入りガラス管に移した。遠心(1500〜000gで10分間)後、血漿サンプルを分析時まで−20℃付近の温度で凍結した。
Ex vivo assay Protocol for administration of formulation to mice:
Prepare the formulation by adding 0.5% Tween 80 and 0.6% methylcellulose to a sufficient final volume in the mortar. Suspensions are administered by gavage (10 ml / kg) to 8-15 week old male Balb / c mice. Three or six hours after a single oral administration of 30 mg / kg, the animals were anesthetized with pentobarbital, and a blood sample (400 μL) was collected from the vena cava and transferred to a glass tube containing lithium heparin. After centrifugation (1500-000 g for 10 minutes), plasma samples were frozen at a temperature around −20 ° C. until analysis.
血漿中の製剤のex vivo活性を検出するために、上記HEK細胞内の自己リン酸化アッセイを使用した。この目的では、トランスフェクションした細胞に化合物の代わりに血漿(10%)を加えてインキュベートした。未処理細胞(最大自己リン酸化)及びトランスフェクションしていない細胞(バックグラウンド)と比較したVEGFR−3自己リン酸化の阻害百分率として結果を表す。 The HEK cell autophosphorylation assay was used to detect the ex vivo activity of the formulation in plasma. For this purpose, transfected cells were incubated with plasma (10%) instead of compound. Results are expressed as percent inhibition of VEGFR-3 autophosphorylation compared to untreated cells (maximum autophosphorylation) and untransfected cells (background).
本発明の化合物のex vivo活性を下表3にまとめる。化合物の経口(p.o.)投与後に(一度に)採取した血漿サンプルの存在下におけるHEK細胞内のVEGFR−3自己リン酸化の阻害百分率として結果を表す。本発明の化合物のこの活性の亢進を評価するために、表3では同一の測定を行った従来技術(WO2009/007535)の化合物と比較する。 The ex vivo activities of the compounds of the present invention are summarized in Table 3 below. Results are expressed as the percentage inhibition of VEGFR-3 autophosphorylation in HEK cells in the presence of plasma samples taken (at a time) after oral (po) administration of the compound. In order to evaluate this enhanced activity of the compounds of the present invention, Table 3 compares to the compounds of the prior art (WO2009 / 007535) that made the same measurements.
以上のように、本発明の化合物はVEGFR−3の自己リン酸化に対する阻害活性をもつため、医薬、特にVEGFR−3を阻害する医薬の製造に使用できることが明らかである。 As described above, since the compound of the present invention has an inhibitory activity against autophosphorylation of VEGFR-3, it is apparent that it can be used for the production of a pharmaceutical, particularly a pharmaceutical that inhibits VEGFR-3.
化合物の暴露、特にバイオアベイラビリティの増加は本発明の化合物によるVEGFR3の自己リン酸化のex vivo阻害を向上させる条件の1つである。 Compound exposure, particularly increased bioavailability, is one condition that improves ex vivo inhibition of VEGFR3 autophosphorylation by the compounds of the present invention.
本発明のVEGFR−3チロシンキナーゼ阻害剤は良好なバイオアベイラビリティを示し、従来技術の阻害剤の1種よりも良好である。 The VEGFR-3 tyrosine kinase inhibitors of the present invention exhibit good bioavailability and are better than one of the prior art inhibitors.
バイオアベイラビリティとは活性部分(薬物又はその代謝物)が全身循環に入って作用部位に到達する割合と速度を意味する。 Bioavailability means the rate and rate at which an active moiety (drug or metabolite) enters the systemic circulation and reaches the site of action.
薬物のバイオアベイラビリティは吸収性を決定する薬物の物理化学的性質によって決定されるのではなく、(そのデザインと製法にも依存する)剤形の性質によって主に決定される。所定の薬物の製剤間のバイオアベイラビリティの差は臨床的に重要であると考えられるため、薬物製剤が等価であるか否かを知ることは不可欠である。 The bioavailability of a drug is not determined by the physicochemical properties of the drug that determine its absorbability, but mainly by the nature of the dosage form (which also depends on its design and process). Because the difference in bioavailability between formulations of a given drug is considered clinically important, it is essential to know whether the drug formulations are equivalent.
バイオアベイラビリティは投与量に対して変化せずに全身循環に到達する薬物の割合を表すために使用され、このような割合は薬物の主要な薬物動態学的性質の1つである。定義によると、医薬を静脈内投与する場合、そのバイオアベイラビリティは100%である。他方、医薬を他の経路(例えば経口)で投与する場合、そのバイオアベイラビリティは(不完全な吸収と初回通過代謝により)低下し、(個体間の変動により)患者間で変動する可能性もある。バイオアベイラビリティは非静脈内投与経路の投与量を計算する際に考慮する必要があるため、薬物動態における必須ツールの1つである。 Bioavailability is used to represent the percentage of drug that reaches the systemic circulation unchanged with respect to dose, and such percentage is one of the major pharmacokinetic properties of the drug. By definition, when a drug is administered intravenously, its bioavailability is 100%. On the other hand, if the drug is administered by other routes (eg, oral), its bioavailability is reduced (due to incomplete absorption and first-pass metabolism) and may vary between patients (due to interindividual variation) . Bioavailability is one of the essential tools in pharmacokinetics because it needs to be taken into account when calculating doses for non-intravenous routes of administration.
従って、別の態様によると、本発明の対象は式(I)の化合物、又は前記化合物と医薬的に許容可能な酸もしくは塩基の付加塩、及びその混合物を含め、式(I)の化合物のエナンチオマーもしくはジアステレオマーを含む医薬である。 Thus, according to another aspect, the subject of the present invention is a compound of formula (I), including a compound of formula (I), or an addition salt of said compound and a pharmaceutically acceptable acid or base, and mixtures thereof. A pharmaceutical containing an enantiomer or diastereomer.
本発明の別の態様は本発明の少なくとも1種の化合物と少なくとも1種の治療剤の併用を含む。 Another aspect of the present invention includes a combination of at least one compound of the present invention and at least one therapeutic agent.
具体的に、本発明の化合物は単独で使用してもよいし、
−アルキル化剤、
−インターカレート剤、
−抗微小管剤、
−抗有糸分裂剤、
−抗代謝剤、
−抗増殖剤、
−抗生剤、
−免疫調節剤、
−抗炎症剤、
−キナーゼ阻害剤、
−抗血管新生剤、
−血管治療剤、
−女性ホルモン及び男性ホルモン
から選択することができる少なくとも1種の治療剤との混合物として使用してもよい。
Specifically, the compounds of the present invention may be used alone or
An alkylating agent,
-Intercalating agents,
-An anti-microtubule agent,
An antimitotic agent,
An antimetabolite,
An antiproliferative agent,
-Antibiotics,
An immunomodulator,
-Anti-inflammatory agents,
A kinase inhibitor,
-Anti-angiogenic agents,
-A vascular therapeutic agent,
-It may be used as a mixture with at least one therapeutic agent which can be selected from female and male hormones.
本発明の化合物を放射線治療と併用することも可能である。 It is also possible to use the compounds of the present invention in combination with radiation therapy.
本発明の化合物と上記治療剤及び/又は放射線の併用も本発明の対象である。 Combinations of the compounds of the present invention with the above therapeutic agents and / or radiation are also subjects of the present invention.
上記治療剤及び/又は放射線は同時、別々又は逐次投与することができる。その治療は治療する患者に応じて医師が調整する。 The therapeutic agent and / or radiation can be administered simultaneously, separately or sequentially. The treatment is adjusted by the physician according to the patient being treated.
これらの医薬は特に、
−癌とその転移(例えば膠芽腫、多発性骨髄腫、骨髄異形成症候群、カポジ肉腫、皮膚血管肉腫、充実性腫瘍、リンパ腫、黒色腫、乳癌、結腸直腸癌、非小細胞癌を含む肺癌、膵臓癌、前立腺癌、腎臓癌、頭頸部癌、肝臓癌、卵巣癌、気道及び胸部癌、VEGFR−3を発現するか又は血管新生もしくはリンパ管新生プロセスを伴う他の腫瘍)の治療及び/又は予防、
−VEGFR−3に関連する非癌性増殖性疾患及び病的血管新生(例えば関節症、再狭窄、乾癬、血管腫、リンパ管腫、緑内障、糸球体腎炎、糖尿病性腎症、腎硬化症、血栓性微小血管障害症候群、肝硬変、アテローム性動脈硬化症、臓器移植拒絶反応、血管新生もしくはリンパ管新生プロセスを伴う眼疾患(例えば糖尿病性網膜症や黄斑変性))の治療及び/又は予防、
−あるいは(慢性又は非慢性)炎症、微生物感染症及び自己免疫疾患(例えば関節リウマチ)の治療及び予防、
−あるいはリンパ脈管筋腫症やゴーハム病等の稀少疾患の治療
において治療薬として使用される。
These medicines are especially
-Cancer and its metastases (eg glioblastoma, multiple myeloma, myelodysplastic syndrome, Kaposi's sarcoma, cutaneous hemangiosarcoma, solid tumor, lymphoma, melanoma, breast cancer, colorectal cancer, lung cancer including non-small cell carcinoma) Treatment of pancreatic cancer, prostate cancer, kidney cancer, head and neck cancer, liver cancer, ovarian cancer, airway and breast cancer, other tumors that express VEGFR-3 or involve angiogenesis or lymphangiogenesis processes) and / or Or prevention,
Non-cancerous proliferative diseases and pathological angiogenesis related to VEGFR-3 (eg arthropathy, restenosis, psoriasis, hemangiomas, lymphangioma, glaucoma, glomerulonephritis, diabetic nephropathy, nephrosclerosis, Treatment and / or prevention of thrombotic microangiopathies syndrome, cirrhosis, atherosclerosis, organ transplant rejection, ocular diseases with angiogenesis or lymphangiogenesis processes (eg diabetic retinopathy and macular degeneration),
-Or treatment and prevention of (chronic or non-chronic) inflammation, microbial infections and autoimmune diseases (eg rheumatoid arthritis),
-Or as a therapeutic agent in the treatment of rare diseases such as lymphangioleiomyomatosis and Gorham's disease .
別の態様によると、本発明は本発明の化合物を有効成分として含有する医薬組成物に関する。これらの医薬組成物は有効量の少なくとも1種の本発明の化合物、又は前記化合物の医薬的に許容可能な塩、水和物もしくは溶媒和物と、少なくとも1種の医薬的に許容可能な賦形剤を含有する。 According to another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention as an active ingredient. These pharmaceutical compositions comprise an effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate of said compound, and at least one pharmaceutically acceptable dose. Contains a dosage form.
前記賦形剤は所望の剤形と投与方法に応じて当業者に公知の通常の賦形剤から選択される。 The excipient is selected from conventional excipients known to those skilled in the art depending on the desired dosage form and administration method.
経口、舌下、皮下、筋肉内、静脈内、外用、局所、気管内、鼻腔内、経皮又は直腸投与用の本発明の医薬組成物では、上記式(I)又は可能なその塩、溶媒和物もしくは水和物の有効成分を上記障害ないし疾患の治療又は予防の目的で動物又はヒトに従来の医薬賦形剤との混合物として単位投与形態で投与することができる。 In the pharmaceutical composition of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, topical, intratracheal, intranasal, transdermal or rectal administration, the above formula (I) or a possible salt or solvent thereof The active ingredient of a hydrate or hydrate can be administered in a unit dosage form as a mixture with a conventional pharmaceutical excipient to animals or humans for the purpose of treating or preventing the above disorders or diseases.
適切な単位投与形態としては、錠剤、ソフト又はハードゼラチンカプセル、散剤、顆粒剤及び経口溶液剤又は懸濁剤等の経口投与形態、舌下、口腔、気管内、眼球内及び鼻腔内投与形態、吸入投与形態、外用、経皮、皮下、筋肉内又は静脈内投与形態、直腸投与形態、並びにインプラントが挙げられる。外用では、本発明の化合物をクリーム、ジェル、軟膏又はローションで使用することができる。 Suitable unit dosage forms include oral dosage forms such as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal dosage forms, Examples include inhaled dosage forms, external, transdermal, subcutaneous, intramuscular or intravenous dosage forms, rectal dosage forms, and implants. For topical use, the compounds of the invention can be used in creams, gels, ointments or lotions.
1例として、錠剤形態の本発明の化合物の単位投与形態は以下の成分を含有することができる:
本発明の化合物 50.0mg
マンニトール 223.75mg
クロスカルメロースナトリウム 6.0mg
コーンスターチ 15.0mg
ヒドロキシプロピルメチルセルロース 2.25mg
ステアリン酸マグネシウム 3.0mg。
By way of example, a unit dosage form of a compound of the invention in tablet form may contain the following ingredients:
50.0 mg of the compound of the present invention
Mannitol 223.75mg
Croscarmellose sodium 6.0mg
Corn starch 15.0mg
Hydroxypropyl methylcellulose 2.25mg
Magnesium stearate 3.0 mg.
別の態様によると、本発明は有効用量の本発明の化合物又はその医薬的に許容可能な塩を患者に投与する段階を含む、上記疾病の治療方法にも関する。 According to another aspect, the present invention also relates to a method for treating the above diseases comprising the step of administering to a patient an effective dose of a compound of the present invention or a pharmaceutically acceptable salt thereof.
Claims (23)
−Wは窒素原子又はCH基を表し;
−Yは1個以上のハロゲン原子を表すR7で場合により置換された、C2−C3アルキニレン基、1,4−フェニレン基を表し;
−Zは結合又はCR1R2基を表し;
−R1及びR2は相互に独立して、水素原子、C1−C6アルキル基、トリフルオロメチル基、(CH2)nOR6基、C3−C7シクロアルキル基、ヘテロアリール基もしくはアリール基から選択される基を表し、ヘテロアリール基もしくはアリール基は場合により1個以上のハロゲン原子で置換される;
−R1及びR2はそれらを担持している炭素原子と一緒になってC3−C7シクロアルキル基を形成してもよく;
−R3は水素原子を表し;
−R4は場合によりC3−C7シクロアルキル基で置換された、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基又はC1−C6アルキル基から選択される基を表し;
−R5は水素原子又はC1−C6アルキル基から選択される基を表し;
−R6は水素原子又はC1−C6アルキル基から選択される基を表し;
−nは1、2又は3である]に対応する塩基又は酸付加塩の形態の化合物。 Formula (I):
-W represents a nitrogen atom or a CH group;
-Y is optionally substituted with R 7 representing a 1 or more halogen atom, C 2 -C 3 alkynylene group, a 1,4-phenylene group;
-Z represents a bond or a CR 1 R 2 group;
-R 1 and R 2 are each independently a hydrogen atom, C 1 -C 6 alkyl group, trifluoromethyl group, (CH 2 ) n OR 6 group, C 3 -C 7 cycloalkyl group, heteroaryl group Or represents a group selected from aryl groups, wherein the heteroaryl group or aryl group is optionally substituted with one or more halogen atoms ;
-R 1 and R 2 together with the carbon atom carrying them may form a C 3 -C 7 cycloalkyl group;
-R 3 represents a hydrogen atom;
-R 4 are substituted by C 3 -C 7 cycloalkyl group optionally, C 1 -C 6 alkyl, (CH 2) n OR 6 group, C 3 -C 7 cycloalkyl group or a C 1 -C 6 Represents a group selected from alkyl groups;
-R 5 represents a group selected from hydrogen atom or a C 1 -C 6 alkyl group;
-R 6 represents a group selected from hydrogen atom or a C 1 -C 6 alkyl group;
-N is 1, 2 or 3] in the form of a base or acid addition salt.
−R1が水素原子、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基、アリール基又は5員もしくは6員ヘテロアリール基から選択される基を表し;
−R2が水素原子、C1−C6アルキル基又はトリフルオロメチル基から選択される基を表し;
−R6が水素原子又はC1−C6アルキル基から選択される基を表し;
−nが1、2又は3である
ことを特徴とする、塩基又は酸付加塩の形態の請求項1から4のいずれか一項に記載の式(I)の化合物。 -Z represents a bond or a CR 1 R 2 group;
-R 1 is a group selected from a hydrogen atom, a C 1 -C 6 alkyl group, a (CH 2 ) n OR 6 group, a C 3 -C 7 cycloalkyl group, an aryl group, or a 5- or 6-membered heteroaryl group. Representation;
-R 2 represents a group selected from hydrogen atom, C 1 -C 6 alkyl or trifluoromethyl groups;
Represents a group -R 6 are selected from hydrogen atom or a C 1 -C 6 alkyl group;
5. A compound of formula (I) according to any one of claims 1 to 4 in the form of a base or acid addition salt, characterized in that -n is 1, 2 or 3.
−R1が水素原子、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基、アリール基又は5員もしくは6員ヘテロアリール基から選択される基を表し;
−R2が水素原子、C1−C6アルキル基又はトリフルオロメチル基から選択される基を表し;
−R6が水素原子又はC1−C6アルキル基から選択される基を表し;
−nが1、2又は3である
ことを特徴とする、塩基又は酸付加塩の形態の請求項1から5のいずれか一項に記載の式(I)の化合物。 -Z represents a CR 1 R 2 group;
-R 1 is a group selected from a hydrogen atom, a C 1 -C 6 alkyl group, a (CH 2 ) n OR 6 group, a C 3 -C 7 cycloalkyl group, an aryl group, or a 5- or 6-membered heteroaryl group. Representation;
-R 2 represents a group selected from hydrogen atom, C 1 -C 6 alkyl or trifluoromethyl groups;
Represents a group -R 6 are selected from hydrogen atom or a C 1 -C 6 alkyl group;
6. A compound of formula (I) according to any one of claims 1 to 5 in the form of a base or acid addition salt, characterized in that -n is 1, 2 or 3.
−Yがハロゲン原子を表すR7で場合により置換された、C2−C3アルキニレン基又は1,4−フェニレン基を表し;
−Zが結合又はCR1R2基を表し;
−R1 が、水素原子、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基、アリール基又は5員もしくは6員ヘテロアリール基から選択される基を表し、アリール基又は5員もしくは6員ヘテロアリール基は場合によりハロゲン原子で置換される;
−R2が水素原子、C1−C6アルキル基又はトリフルオロメチル基から選択される基を表し;
−R3が水素原子を表し;
−R4が場合によりC3−C7シクロアルキル基で置換された、C1−C6アルキル基、(CH2)nOR6基、C3−C7シクロアルキル基又はC1−C6アルキル基から選択される基を表し;
−R5が水素原子又はC1−C6アルキル基から選択される基を表し;
−R6が水素原子又はC1−C6アルキル基から選択される基を表し;
−nが1、2又は3である
ことを特徴とする、塩基又は酸付加塩の形態の請求項1から9のいずれか一項に記載の式(I)の化合物。 -W represents a nitrogen atom or a CH group;
-Y is optionally substituted with R 7 represents a halogen atom, a C 2 -C 3 alkynylene group or a 1,4-phenylene group;
-Z represents a bond or a CR 1 R 2 group;
-R 1 is a group selected from a hydrogen atom, a C 1 -C 6 alkyl group, a (CH 2 ) n OR 6 group, a C 3 -C 7 cycloalkyl group, an aryl group, or a 5-membered or 6-membered heteroaryl group An aryl group or a 5- or 6-membered heteroaryl group is optionally substituted with a halogen atom ;
-R 2 represents a group selected from hydrogen atom, C 1 -C 6 alkyl or trifluoromethyl groups;
-R 3 is hydrogen;
-R 4 is substituted with a C 3 -C 7 cycloalkyl group optionally, C 1 -C 6 alkyl, (CH 2) n OR 6 group, C 3 -C 7 cycloalkyl group or a C 1 -C 6 Represents a group selected from alkyl groups;
-R 5 are radicals represents a group selected from hydrogen atom or a C 1 -C 6 alkyl group;
Represents a group -R 6 are selected from hydrogen atom or a C 1 -C 6 alkyl group;
10. A compound of formula (I) according to any one of claims 1 to 9 in the form of a base or acid addition salt, characterized in that -n is 1, 2 or 3.
2−アミノ−1−プロピル−7−((3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−7−(3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−(3−ヒドロキシ−3−ピリジン−2−イルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−[(3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル]−3−(4−メチル−1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−(シクロプロピルメチル)−7−(3−ヒドロキシペンタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−[(3R)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル]−3−(1H−イミダゾール−2−イル)−1H−キノリン−4−オン、
2−アミノ−7−(3−クロロ−4−ヒドロキシフェニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−[3−(2−フルオロフェニル)−3−ヒドロキシブタ−1−イニル]−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−シクロペンチル−7−(3−ヒドロキシペンタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−7−(3−ヒドロキシペンタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1−(3−メトキシプロピル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−7−(3−ヒドロキシペンタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1−(2−メトキシエチル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−[(1−ヒドロキシシクロブチル)エチニル]−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−[(1−ヒドロキシシクロペンチル)エチニル]−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−(3−ヒドロキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−(3−ヒドロキシ−3−メチルペンタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−(3−ヒドロキシ−3−フェニルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−[3−(3−フルオロフェニル)−3−ヒドロキシブタ−1−イニル]−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−3−(1H−イミダゾール−2−イル)−7−(4,4,4−トリフルオロ−3−ヒドロキシ−3−フェニルブタ−1−イニル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−7−(3−シクロプロピル−3−ヒドロキシブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−[3−ヒドロキシ−3−(チオフェン−2−イル)ブタ−1−イニル]−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−(3−ヒドロキシブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−(3−ヒドロキシペンタ−1−イニル)−3−(1H−
イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−(3−ヒドロキシ−ヘキサ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−(3−ヒドロキシ−4−メチルペンタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−1−エチル−7−(3−ヒドロキシ−3−フェニルプロパ−1−イニル)−3−(1H−イミダゾール−2−イル)−1H−[1,8]ナフチリジン−4−オン、
2−アミノ−7−((3R)−3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン、
2−アミノ−7−((3S)−3,4−ジヒドロキシ−3−メチルブタ−1−イニル)−1−エチル−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン、
2−アミノ−1−エチル−7−((3S)−3−ヒドロキシ−4−メトキシ−3−メチルブタ−1−イニル)−3−(1H−イミダゾール−2−イル)−1,8−ナフチリジン−4(1H)−オン
から選択される、請求項1に記載の式(I)の化合物。 2-Amino-1-ethyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8 Naphthyridin-4-one,
2-Amino-1-propyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8 Naphthyridin-4-one,
2-Amino-7- (3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one ,
2-Amino-1-ethyl-7- (3-hydroxy-3-pyridin-2-ylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine-4 -On,
2-Amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl] -3- (4-methyl-1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1- (cyclopropylmethyl) -7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl] -3- (1H-imidazol-2-yl) -1H-quinoline-4- on,
2-amino-7- (3-chloro-4-hydroxyphenyl) -1-ethyl-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-1-ethyl-7- [3- (2-fluorophenyl) -3-hydroxybut-1-ynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine -4-one,
2-amino-1-cyclopentyl-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1- (3-methoxypropyl) -1H- [1,8] naphthyridin-4-one ,
2-Amino-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1- (2-methoxyethyl) -1H- [1,8] naphthyridin-4-one ,
2-amino-1-ethyl-7-[(1-hydroxycyclobutyl) ethynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7-[(1-hydroxycyclopentyl) ethynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-3-methylpent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-3-phenylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-1-ethyl-7- [3- (3-fluorophenyl) -3-hydroxybut-1-ynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine -4-one,
2-Amino-1-ethyl-3- (1H-imidazol-2-yl) -7- (4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-ynyl) -1H- [1 , 8] naphthyridin-4-one,
2-Amino-7- (3-cyclopropyl-3-hydroxybut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one ,
2-Amino-1-ethyl-7- [3-hydroxy-3- (thiophen-2-yl) but-1-ynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] Naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxybut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-1-ethyl-7- (3-hydroxypent-1-ynyl) -3- (1H-
Imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-hex-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-4-methylpent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-3-phenylprop-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-7-((3R) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridine-4 ( 1H) -on,
2-Amino-7-((3S) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridine-4 ( 1H) -on,
2-Amino-1-ethyl-7-((3S) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1,8-naphthyridine 2. A compound of formula (I) according to claim 1 selected from 4 (1H) -one.
又は一般式(XVb):
義した通りである]の化合物と反応させ、
式(VII)の化合物を一般式(XVa)の化合物又は一般式(XVb)の化合物と反応させる前又は後に通常の脱保護工程を実施することを特徴とする、方法。 A process for the preparation of a compound of formula (I) according to any one of claims 1 to 12 , comprising formula (VII):
Or general formula (XVb):
A process characterized by carrying out a normal deprotection step before or after reacting a compound of formula (VII) with a compound of general formula (XVa) or a compound of general formula (XVb).
−アルキル化剤、
−インターカレート剤、
−抗微小管剤、
−抗有糸分裂剤、
−抗代謝剤、
−抗増殖剤、
−抗生剤、
−免疫調節剤、
−抗炎症剤、
−キナーゼ阻害剤、
−抗血管新生剤、
−血管治療剤、
−女性ホルモン及び男性ホルモン
から選択される少なくとも1種の治療剤を含む医薬組成物。 A compound of formula (I) according to any one of claims 1 to 12 , and
An alkylating agent,
-Intercalating agents,
-An anti-microtubule agent,
An antimitotic agent,
An antimetabolite,
An antiproliferative agent,
-Antibiotics,
An immunomodulator,
-Anti-inflammatory agents,
A kinase inhibitor,
-Anti-angiogenic agents,
-A vascular therapeutic agent,
-A pharmaceutical composition comprising at least one therapeutic agent selected from female and male hormones.
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JP6226981B2 (en) * | 2012-07-17 | 2017-11-08 | サノフイ | Use of a VEGFR-3 inhibitor to treat hepatocellular carcinoma |
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Publication number | Priority date | Publication date | Assignee | Title |
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JP2015522598A (en) * | 2012-07-17 | 2015-08-06 | サノフイ | Use of a VEGFR-3 inhibitor to treat hepatocellular carcinoma |
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